Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies.

Introduction

The tumor suppressor protein p53, encoded by the TP53 gene, plays a vital role in regulating cellular responses to stress and maintaining genomic integrity [ 1 – 3 ]. As a key transcription factor, p53 integrates signals from DNA damage, oncogenic stress, and metabolic imbalances to manage essential processes such as cell cycle arrest, DNA repair, cellular senescence, and apoptosis [ 4 – 7 ]. Through these functions, p53 acts as a crucial barrier against malignant transformation. The signals that trigger stress and activate p53, along with the resulting cellular outcomes, are illustrated in Fig. 1 .

Fig. 1 Overview of p53-regulated stress responses and therapeutic entry points. Schematic illustration of the major cellular stress signals that activate p53, including DNA damage, oncogene activation, hypoxia, and metabolic stress, and the downstream transcriptional programs governing cell cycle arrest, DNA repair, senescence, and apoptosis. Central to these responses is the regulation of p53 stability and activity by post-translational modifications, particularly ubiquitination mediated by E3 ligases and deubiquitinases. This framework provides a conceptual reference for the therapeutic strategies discussed throughout this review, including p53 reactivation, mutant p53 degradation, exploitation of synthetic lethal vulnerabilities, and targeting of downstream p53-regulated pathways

TP53 plays a crucial role in the body, but it is also the most frequently mutated gene in human cancer, with alterations found in about half of all tumors [ 1 , 2 ]. Unlike many tumor suppressor genes that are often deleted or silenced, TP53 is typically affected by missense mutations [ 4 ]. These mutations lead to the production of unstable proteins that still get expressed. As a result, mutant p53 proteins lose their normal tumor suppressor function and may exert dominant-negative effects on wild-type p53 family members. Additionally, these mutants can acquire gain-of-function properties that promote tumor progression, metastasis, and resistance to therapy [ 5 ].

The prevalence and functional diversity of TP53 mutations have significant implications for cancer therapy. Tumors with TP53 mutations are often linked to poor prognosis and resistance to chemotherapy, radiotherapy, and targeted treatments. However, the stability and persistence of mutant p53 proteins also present unique therapeutic opportunities. Over the past decade, considerable progress has been made in developing strategies to restore wild-type p53 function, eliminate mutant p53, or exploit vulnerabilities arising from p53 loss.

The purpose of this review is to critically evaluate emerging therapeutic strategies targeting p53. We will focus on how different TP53 mutation types affect treatment responses and highlight recent advances in gene therapy, small-molecule reactivation, targeted degradation, synthetic lethality, and modulation of downstream pathways. Drawing on extensive research from our laboratory and others regarding the regulation of p53 stability by ubiquitin ligases and related pathways, we aim to provide a comprehensive framework for understanding how mutant p53 can be transformed from a contributor to poor prognosis into a viable therapeutic target [ 6 – 8 ]. Unlike many previous p53 reviews that emphasize canonical loss-of-function paradigms, this review highlights dominant-negative and gain-of-function mechanisms, structural and oligomerization-based interference, and their emerging therapeutic implications.

The guardian’s dilemma: understanding p53 mutations

The integrity of the p53 pathway is crucial for maintaining genome stability and preventing malignant transformation. The TP53 gene exhibits a distinctive mutation spectrum in human cancers, characterized by a high frequency of missense mutations clustered within the DNA-binding domain [ 4 , 9 , 10 ]. These alterations not only disrupt the canonical tumor suppressor functions of p53 but can also confer dominant-negative or gain-of-function activities that actively promote tumor progression. Understanding the diversity of TP53 mutations, their structural consequences, and their biological impact is essential for appreciating how they reshape the cancer landscape and complicate therapeutic intervention. The structural domains of p53 and the distribution of hotspot mutations are illustrated in Fig. 2 .

Fig. 2 Schematic representation of TP53 domains and recurrent cancer-associated mutations. Full-length TP53 (1–393 aa) is shown with major functional domains indicated: transactivation (1–61), proline-rich (62–94), DNA-binding (95–292), oligomerization (323–356), and C-terminal regulatory domain (357–393). Recurrent hotspot mutations within the DNA-binding domain are displayed using a lollipop plot, where vertical stems indicate mutation positions and circles denote individual mutations. Conformational mutations (R175H, Y220C) and DNA-contact mutations (R248Q/W, R273H/C, R282W) are highlighted in distinct colors. Collectively, these mutations disrupt normal p53 function and contribute to tumorigenesis

Types of p53 mutations

Mutations in TP53 can be classified into several categories, each with distinct effects on the protein’s structure and function. (1) p53 missense mutations account for approximately 75% of all TP53 gene alterations [ 5 ]. These mutations typically occur within the DNA-binding domain, specifically in exons 5 to 8, and lead to single-amino acid substitutions that disrupt sequence-specific DNA recognition [ 11 – 15 ]. R175, G245, R248, R273, and R282 are significant p53 hotspot mutations that frequently occur across various tumor types. R175 refers to the substitution of arginine at position 175 with other amino acids, located within a loop that interacts with DNA. Mutations at R175 destabilize the DNA-binding domain, significantly impairing p53’s ability to suppress tumors. The R175H mutation, which changes arginine to histidine, is common and is often associated with gain-of-function properties that promote invasion and metastasis [ 16 ]. G245 is located in the L3 loop of the DNA-binding domain, a crucial area for DNA interaction. Mutations like G245S (glycine to serine) can disrupt the loop’s structure and hinder DNA binding [ 17 ]. R248 is a frequently mutated codon in the TP53 gene, essential for binding to the major groove of DNA. Mutations such as R248Q (arginine to glutamine) and R248W (arginine to tryptophan) disrupt these interactions, preventing p53 from binding to its target genes. R248 mutants are known for their gain-of-function activities, which promote increased cell proliferation, survival, and metastatic potential [ 11 , 18 ]. R249, located next to R248, is a key DNA-contact residue. The R249S mutation (arginine to serine) is common in hepatocellular carcinoma and linked to exposure to aflatoxin B1, a potent carcinogen. This mutation disrupts DNA binding and is often associated with more aggressive disease [ 19 ]. R273 is a key residue that interacts with the phosphate backbone of DNA, stabilizing the p53-DNA complex. Mutations at R273, such as R273H, significantly reduce DNA-binding affinity, thereby impairing p53’s ability to activate target genes [ 20 ]. R282 is located in an alpha-helix of the DNA-binding domain and interacts non-sequence-specifically with DNA. Mutations such as R282W (arginine to tryptophan) disrupt the structure of this helix, compromising the domain’s stability and leading to loss of p53 function [ 21 ]. (2) Nonsense mutations of the TP53 gene account for approximately 10–11% of all TP53 mutations. These mutations introduce a premature termination codon (PTC) into the messenger RNA (mRNA) sequence, resulting in the production of a truncated and inactive p53 protein [ 22 ]. These often result in complete loss of p53 activity and contribute to haploinsufficiency or null phenotypes. Here are two examples of nonsense mutations in the TP53 gene: (a) TP53 p.R213X (c.637 C > T). This common mutation converts arginine (R) to a premature stop codon (X) at amino acid position 213, resulting in a non-functional p53 protein [ 22 ]. (b) TP53 p.R306X (c.916 C > T). This mutation introduces a premature stop codon at position 306, leading to a nonfunctional p53 protein and a failure to induce apoptosis in TP53 -null cells [ 23 ]. (3) Frameshift mutations arise from insertions or deletions that alter the reading frame, leading to the production of unstable or misfolded proteins. For example, (a) The TP53 c.216dup (p.Val73fs) mutation is a specific type of frameshift mutation characterized by the duplication of a single nucleotide (cytosine, C) at position 216 of the TP53 cDNA (c.216dupC). This mutation is predicted to lead to a loss of normal protein function and has been classified as pathogenic. It is associated with hereditary cancer syndromes, such as Li-Fraumeni Syndrome [ 24 ]. (b) TP53 c.994_995delTC (p.Cys332Ilefs*14). This frameshift mutation is caused by the deletion of two nucleotides (TC) at positions 994–995 in the TP53 cDNA. This alteration results in a change from cysteine to isoleucine at amino acid 332, followed by a premature stop codon 14 amino acids downstream (p.Cys332Ilefs*14). Although this mutation primarily leads to a loss of transcriptional activity, it retains residual antiproliferative effects and can induce cellular senescence [ 25 ]. (4) Splice-site mutations in the TP53 gene are genetic changes that occur at the junctions between exons and introns, disrupting the normal splicing process of mRNA. When these mutations occur in TP53 , they can lead to abnormal splicing, resulting in the production of non-functional or truncated p53 proteins. This disruption compromises the protein’s essential role as a tumor suppressor. Examples of TP53 splice-site mutations: (a) TP53 c.375 + 1G > A: This somatic splice mutation affects a splice donor site in intron 3 (or the + 1 position of intron 4) of the TP53 gene. It leads to a truncated protein that lacks essential coding sequences, including the DNA-binding and oligomerization domains, rendering it non-functional. This mutation is associated with various cancers, such as high-grade serous ovarian cancer, breast cancer, and bladder cancer [ 26 ]. (b) TP53 c.560-1G > C (IVS05-1G > C) is a pathogenic splice-site mutation involving a G to C substitution just before coding exon 5, at the acceptor splice site of intron 4. This change disrupts RNA splicing, typically resulting in a loss of protein function. It has been associated with Li-Fraumeni Syndrome and rhabdomyosarcoma [ 27 ]. (5) Deletions and large genomic rearrangements of TP53 gene are significant alterations that compromise the p53 protein. Unlike point mutations, which modify specific nucleotides, deletions remove entire DNA segments, while large rearrangements involve complex structural changes, such as inversions or translocations. These substantial changes are frequently seen in human cancers and are often linked to more aggressive disease forms. (a) Deletion of chromosome 17p. This is a well-known example of a TP53 gene alteration located on the short arm of chromosome 17 (17p13.1), including chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), glioblastoma, and colorectal cancer. It often leads to the loss of one TP53 allele and usually a point mutation in the other, resulting in the complete inactivation of the p53 protein [ 28 , 29 ]. (b) Large deletions encompassing the entire TP53 gene in Li-Fraumeni Syndrome (LFS). These large deletions increase the high cancer risk associated with LFS patients and are linked to more aggressive cancer characteristics [ 30 , 31 ]. (c) Recurrent genomic rearrangements in intron 1 of TP53 in osteosarcoma. Beyond simple deletions, complex genomic rearrangements, specifically recurrent rearrangements within intron 1 of the TP53 gene, have been identified as a mechanism of TP53 inactivation in osteosarcoma. These rearrangements can occur somatically in sporadic cases or as germline events leading to LFS. Whole-genome sequencing has revealed that these structural variations are particular to osteosarcoma [ 32 ]. Table 1 summarizes major TP53 mutation classes and representative, clinically relevant hotspot mutations discussed in the text and is not intended to provide an exhaustive catalog of all TP53 variants.

Table 1 TP53 mutation classes with representative hotspot mutations and therapeutic implications Mutation Class Representative Hotspot Mutations Structural / Biochemical Impact DNE / GOF Tendency Typical Cancers Therapeutic Implications Contact R248Q/W, R273H/C, R282W Loss of sequence-specific DNA binding Strong DNE; context-dependent GOF Colon, Lung, H&N Variable reactivation; checkpoint targeting [ 20 , 37 - 43 ] Conformational R175H, Y220C Zinc coordination loss / crevice formation Frequent GOF; aggregation-prone Breast, Ovary, Sarcoma Zinc metallochaperones; stabilizers [ 16 , 155 , 243 ] Truncating Nonsense, frameshift Null or severely truncated protein Minimal DNE / GOF Multiple Treated as p53-null; exploit DDR [ 22 - 25 ] Splice / Isoform Δ40p53, Δ133p53 Altered domains / regulation Context-dependent Variable Prognostic nuance [ 26 , 27 , 61 ] LOH / Deletion WT allele loss Increased mutant dosage Amplified GOF Aggressive tumors Biomarker of poor outcome [ 28 - 32 ]

Structural disruption and loss of DNA binding

The central DNA-binding domain (residues 100–300) is essential for p53’s transcriptional activity. Mutations in this domain can be categorized into two major types: (1) Conformational (structural) mutants. Unlike contact mutants that affect DNA-binding residues, conformational mutants affect the structural integrity and stability of p53, especially in its DNA-binding domain (DBD) [ 33 , 34 ]. Even a single amino acid change can cause significant misfolding, hindering its ability to bind to target DNA sequences effectively. p53 R175H exhibits dominant-negative effects over wild-type p53 by forming mixed tetramers that inactivate functional proteins, thereby promoting tumor progression. Its presence is often associated with poor prognosis and resistance to conventional therapies [ 16 , 35 , 36 ]. ( 2 ) Contact mutants of p53 . R248Q and R273H are notable contact mutants of the p53 tumor suppressor protein that impair its ability to bind to DNA response elements. As a well-documented gain-of-function (GOF) mutation, R248Q not only loses tumor suppressor activity but also promotes tumor progression, metastasis, and drug resistance. Its GOF activities may alter gene expression related to cell proliferation and survival, and modify metabolic pathways [ 20 , 37 – 40 ]. R273H is a well-characterized GOF mutant that promotes cancer progression and modifies cellular metabolism to support tumor growth. It is associated with aggressive tumor characteristics, increased metastatic potential, and resistance to standard cancer therapies [ 20 , 41 – 43 ].

Dominant-negative TP53 mutations and their role in human disease

p53 functions as a tetrameric transcription factor, with oligomerization required for DNA binding and gene activation [ 44 – 47 ]. This structural requirement underlies the biological significance of dominant-negative (DN) mutations, in which a defective p53 protein interferes with the function of the wild-type allele. Such effects are particularly consequential for tumor suppressors like TP53 , where DN inhibition can severely compromise pathway activity even in heterozygous settings [ 12 , 48 – 50 ]. Dominant-negative p53 proteins reduce the effective pool of functional p53 [ 36 ], accelerate tumorigenesis [ 41 , 51 ], and may facilitate the emergence of gain-of-function (GOF) phenotypes [ 52 – 54 ]. Therefore, therapeutic strategies aimed at restoring p53 activity must account for both loss of wild-type function and active inhibition by mutant p53.

Mechanistically, dominant-negative suppression arises primarily through hetero-oligomerization, whereby mutant p53 subunits incorporate into mixed tetramers, thereby disrupting their stability and DNA-binding capacity. Notably, the C-terminal oligomerization domain of p53 is itself sufficient to exert dominant-negative effects, emphasizing the importance of tetramer integrity in p53 regulation [ 55 ]. Experimental studies have shown that expression of C-terminal p53 fragments containing the oligomerization domain can inhibit wild-type p53 function, highlighting the relevance of mutations or alterations affecting this region [ 56 – 58 ].

Consistent with these mechanistic principles, TP53 is the most commonly mutated gene in human cancer, with missense mutations accounting for approximately 70–75% of all alterations [ 4 , 59 ]. Many of these missense variants encode full-length proteins that oligomerize and therefore exhibit dominant-negative activity [ 48 , 60 ]. Dominant-negative mutations are highly enriched at recurrent hotspot residues within the DNA-binding domain, including R175, G245, R248, R249, R273, and R282 [ 4 , 59 ], and are prevalent across a broad spectrum of malignancies, including breast, colorectal, lung, ovarian, head and neck cancers, glioblastoma, and hematological malignancies [ 4 ]. In addition to missense mutations, dominant-negative suppression of p53 can also arise from specific p53 isoforms generated by alternative splicing or translation. Isoforms such as Δ40p53 and Δ133p53 retain the oligomerization domain but lack full transactivation potential, enabling them to form mixed tetramers with full-length p53 and attenuate its transcriptional activity [ 61 ].

Structurally, dominant-negative TP53 mutations can be broadly categorized into two classes: (i) Conformational mutants (e.g., R175H, G245S, R282W), which destabilize the p53 core domain and impair proper folding; and (ii) DNA-contact mutants (e.g., R248Q/W, R273H), which retain overall structural integrity but directly disrupt sequence-specific DNA binding [ 62 ]. Despite distinct molecular defects, both classes preserve oligomerization capacity and efficiently inhibit wild-type p53 through formation of inactive mixed tetramers [ 48 , 62 ].

Clinically, dominant-negative TP53 mutations are associated with early tumor development, aggressive disease progression, poor prognosis, and resistance to chemotherapy and radiotherapy [ 4 , 63 ]. In breast and colorectal cancers, patients harboring dominant-negative TP53 mutations exhibit worse clinical outcomes than those with TP53 -null tumors, suggesting that dominant-negative interference may be more deleterious than complete loss of p53 function [ 63 ]. The pathological impact of dominant-negative TP53 mutations is further underscored in Li–Fraumeni syndrome, where germline missense mutations frequently encode dominant-negative p53 proteins, conferring exceptionally high lifetime cancer risk and early-onset malignancies, including sarcomas, breast cancers, brain tumors, and leukemias [ 64 ].

Together, dominant-negative TP53 mutations represent a distinct and clinically significant class of p53 alterations, defined by active suppression of residual wild-type p53 rather than passive loss of function. Their prevalence across cancer types and association with adverse clinical outcomes underscore the importance of therapeutic approaches that either counteract dominant-negative inhibition, reactivate wild-type p53, or selectively eliminate mutant p53 [ 63 ].

Gain-of-Function (GOF) activities of p53 mutations

GOF activities of p53 mutations refer to a phenomenon where mutant p53 proteins not only lose their original tumor suppressor functions but also acquire novel, oncogenic properties that actively promote cancer development and progression. This concept significantly expands our understanding of TP53 ’s role in cancer beyond simply being a “loss-of-function” tumor suppressor. These GOF properties contribute directly to the malignant phenotype, often by mechanisms independent of their normal DNA-binding and transcriptional functions [ 56 , 64 – 66 ].

GOF activities in p53 mutations are significant for several reasons: (1) Enhanced malignancy. GOF mutant p53 proteins can lead to more aggressive tumors, increased growth rates, and greater resistance to cell death. (2) Therapeutic challenge. Simply restoring wild-type p53 function may not be sufficient, as the mutant protein’s oncogenic activities can continue promoting tumor growth. Therapies must target both the reactivation of wild-type p53 and the inhibition of GOF functions. (3) Prognostic indicator. Specific GOF p53 mutations are often associated with more aggressive tumors, greater metastatic potential, and poorer patient outcomes. (4) Novel therapeutic targets. Research is ongoing into strategies that target mutant p53 proteins or their downstream effects as potential therapies.

In addition to loss of tumor suppressive activity, many missense p53 mutants acquire GOF properties that actively promote tumor progression. A well-established GOF mechanism involves aberrant interactions between mutant p53 and the p53 family members p63 and p73. Multiple studies have shown that mutant p53 proteins bind and sequester p63 and p73, thereby inhibiting their transcriptional programs governing apoptosis, differentiation, and genomic stability [ 67 – 69 ]. This dominant-negative interference contributes to enhanced invasion, metastasis, and chemoresistance across multiple cancer types and is widely regarded as a core component of mutant p53 GOF biology. The regulation of p63 and p73 isoforms is complex, involving intricate control by E3 ligases and molecular chaperones such as Hsp70, which dictate their stability and activity [ 70 ]. Furthermore, our work has shown that p63 itself is a key regulator of microRNA processing through its interaction with Ago2, linking this tumor suppressor family directly to post-transcriptional gene regulation [ 71 ]. The sequestration of these family members by mutant p53 disrupts these critical functions. Mutant p53 has the ability to change the transcription of genes that are not typically associated with wild-type p53 targets. This may involve binding to new DNA sequences, interacting with other transcription factors such as NF-Y and SP1, or recruiting enzymes that modify chromatin. These actions can activate oncogenic pathways or suppress tumor-suppressive pathways [ 72 ]. Some GOF mutants have been demonstrated to reprogram cellular metabolism, enhancing glycolysis and glutaminolysis, which are critical for the rapid proliferation of cancer cells [ 73 – 75 ]. Mutant p53 contributes to increased genomic instability, leading to additional mutations and chromosomal rearrangements that drive tumor evolution [ 76 – 78 ]. GOF mutants can enhance cell migration, invasion, and metastatic spread by upregulating genes associated with epithelial-mesenchymal transition (EMT), angiogenesis, and extracellular matrix remodeling [ 79 – 81 ]. Many common “hotspot” missense mutations in TP53 are known to exhibit significant GOF, such as p53 R175H [ 41 ], p53 R248Q [ 82 ], and p53 R273H [ 83 ]. The p53R175H mutation is frequently classified as dominant-negative because it interferes with wild-type p53 function by hetero-oligomerization. However, extensive experimental evidence has also demonstrated that p53R175H exhibits gain-of-function properties, including activation of oncogenic transcriptional programs and promotion of invasion and metastasis in p53-null or mutant contexts [ 83 , 84 ]. Thus, R175H is widely regarded as a mutation with dual dominant-negative and gain-of-function activities, depending on cellular context and p53 allelic status.

Importantly, these GOF effects are context-dependent, varying across cancer types and mutation hotspots. The concept of mutant p53 as an “oncoprotein” has changed our understanding of TP53 ; it is not just a “loss-of-function” gene but also a contributor to cancer aggressiveness. As illustrated in Fig. 3 , dominant-negative and gain-of-function mutant p53 activities reshape transcriptional programs, chromatin states, and downstream signaling pathways, creating vulnerabilities that can be targeted for therapeutic intervention.

Fig. 3 Dominant-negative and gain-of-function mechanisms of mutant p53. Mutant p53 proteins impede wild-type p53 function through two main mechanisms: (1) Dominant-negative effect (DNE): Hybrid tetramers formed by wild-type and mutant p53 reduce DNA-binding ability, leading to decreased transcription of target genes like p21, BAX, and PUMA. (2) Gain-of-Function (GOF): Mutant p53 gains new oncogenic traits through interactions with p63 and p73, resulting in transcriptional changes, chromatin remodeling (via SWI/SNF complexes), and activation of processes that promote invasion, epithelial–mesenchymal transition (EMT), drug resistance, and metabolic reprogramming

The E3 ligase network: a complex web of p53 regulators beyond MDM2

Mdm2 (MDM2 or Hdm2 in humans) is a key negative regulator of the p53 protein [ 85 , 86 ]. Loss of Mdm2 in mice results in an embryonic-lethal phenotype. However, this early embryonic lethality in Mdm2-null mice is rescued by deleting the p53 gene, indicating the importance of Mdm2’s negative regulatory function on p53 during development [ 87 , 88 ]. MDM2 mediates mono- or multiple ubiquitination of p53 [ 89 ], but only polyubiquitin chains are efficiently recognized by the proteasome [ 8 ]. MDM4, also known as MDMX, is a close homolog of MDM2 and a crucial regulator of the tumor suppressor protein p53 [ 90 ]. Although MDM4 lacks intrinsic E3 ligase activity, it forms heterodimers with MDM2, which stabilizes MDM2 and enhances its E3 ligase function toward p53 [ 91 ]. Genetic studies have shown that Mdm4 deletion results in p53-dependent embryonic lethality, highlighting its essential role in regulating p53 activity during development [ 92 , 93 ]. In contrast to the MDM2/MDM4 complex, Pirh2 is a p53-inducible E3 ligase that ubiquitinates p53 mainly as part of a negative feedback loop. While Pirh2 contributes to p53 turnover, it does not mimic the effects of Mdm2 or Mdm4 loss in vivo and appears to play a more context-dependent or stress-responsive role [ 94 ]. We provide evidence that Pirh2 is a critical negative regulator of p53 and represents a new pathway for maintaining p53. Additionally, Pirh2 regulates other p53 family members, such as p73, and its stability and activity can be modulated by the E3 ligase AIP4 [ 95 , 96 ]. Currently, Pirh2 is not considered a clinically targetable E3 ligase, and no selective small-molecule inhibitors of Pirh2 have been reported. Unlike MDM2, Pirh2 lacks a well-defined ligandable pocket analogous to the p53-binding cleft of MDM2, and its catalytic RING domain presents substantial challenges for selective pharmacologic inhibition.

Genetic studies further distinguish Pirh2 from MDM2/MDM4. Pirh2 knockout mice are viable and do not display embryonic lethality, in contrast to the p53-dependent lethality observed in Mdm2- or Mdm4-null animals [ 97 ]. Pirh2-deficient mice exhibit relatively mild phenotypes, including altered p53 responses under specific stress conditions, supporting the view that Pirh2 functions as a context-dependent or auxiliary regulator of p53, rather than a dominant, non-redundant suppressor [ 97 ]. Together, these observations suggest that while Pirh2 contributes to fine-tuning p53 signaling, it is currently less attractive as a therapeutic target than the MDM2/MDM4 axis. Therefore, MDM2, with the support of MDM4, serves as the primary, non-redundant E3 ligase responsible for maintaining p53 suppression and facilitating its proteasome-mediated degradation. Furthermore, UBE4B is essential and required for MDM2-mediated p53 polyubiquitination and degradation [ 8 ]. UBE4B mediates not only p53 polyubiquitination and degradation, but also inhibits p53-dependent transactivation and apoptosis.

Clinical associations of p53 mutations

The associations of TP53 mutations in clinical settings are crucial because they act as significant prognostic and predictive biomarkers across various human cancers. Mutations in p53 predict the likely course and outcome of disease for a patient, regardless of treatment [ 98 – 100 ]. Specific p53 mutations can predict how patients will respond to particular therapies, such as chemotherapy, radiation, targeted agents, and immunotherapy. This allows for more personalized and effective treatment strategies [ 101 , 102 ]. Identifying individuals with p53 mutations can help determine who might benefit from more aggressive treatment approaches or closer surveillance [ 103 , 104 ]. Mutations in p53 guide the development of new drugs that specifically target cells with mutant p53 or aim to restore wild-type p53 function [ 34 , 105 ].

Mutations in TP53 gene are present in nearly all human cancers, but they vary in prevalence and clinical significance across different cancer types. For example, in breast cancer, mutations in p53 gene are frequently associated with triple-negative breast cancer subtypes. The presence of mutant p53 is connected to a worse prognosis for patients [ 106 , 107 ]. TP53 is the most frequently mutated gene in NSCLC, found in about 50% of adenocarcinomas and over 80% of squamous cell carcinomas [ 108 – 110 ]. TP53 mutations are frequently observed in colorectal cancer, especially in later stages and specific molecular subtypes. Their presence typically correlates with a poorer prognosis [ 111 – 113 ]. Mutations in TP53 gene play a significant role in the resistance to therapy and the recurrence of glioblastoma [ 114 – 116 ]. High-grade serous carcinoma in ovarian cancer shows TP53 mutations in over 95% of cases, underscoring its critical role [ 117 – 119 ]. Li-Fraumeni Syndrome is associated with germline mutations in the TP53 gene, which significantly increase the risk of various cancers, including sarcomas, breast cancer, and brain tumors. This underscores the vital role of functional p53 in tumor suppression [ 120 , 121 ].

These examples demonstrate the diverse effects of p53 mutations — from sporadic somatic events that influence tumor evolution to inherited mutations that contribute to cancer predisposition syndromes. These mechanistic insights provide essential context for understanding how TP53 mutations influence therapeutic response, as discussed in the following sections.

A weakened shield: impact of p53 mutations on cancer therapy

Unlike prior reviews that focused on mechanistic aspects of p53 dysfunction, this section emphasizes recent translational and clinical evidence linking TP53 status to therapeutic response. Loss or mutation of p53 profoundly alters tumor responses to therapy. Wild-type p53 coordinates cell cycle arrest, DNA repair, and apoptosis in response to therapeutic stress, whereas TP53 mutations disable these safeguards, allowing cancer cells to survive and adapt under treatment pressure. Clinically, TP53 mutations are associated with therapy resistance, disease progression, and poor patient outcomes across many tumor types.

TP53 mutations and response to genotoxic and targeted therapies

TP53 status plays a crucial role in determining tumor sensitivity to chemotherapy and radiotherapy [ 5 , 122 ]. Tumors that retain wild-type p53 typically respond better to DNA-damaging agents due to p53-dependent mechanisms, such as cell cycle arrest and apoptosis. In contrast, tumors with TP53 mutations often show either intrinsic or acquired resistance to these treatments [ 123 , 124 ]. Similarly, the effectiveness of several targeted therapies is influenced by p53 status, particularly those targeting DNA damage response pathways or angiogenic signaling. Instead of providing an exhaustive review of these well-established relationships, we summarize overarching therapeutic strategy categories influenced by TP53 mutations (Table 2 ) rather than disease-specific clinical outcome data.

Table 2 Established therapeutic strategies influenced by TP53 mutation status Strategy Modality Example agents/approaches Development stage Key considerations Reactivation Small molecules APR-246, ZMC1, PC14586 Phase II/III and preclinical Mutation-dependent efficacy; combinations often needed [ 153 , 157 , 243 ] Degradation Chaperone/HDAC disruption 17-AAG/ganetespib; Panobinostat Early clinical / combination Broad effects; toxicity windows matter [ 160 - 165 ] PROTACs p53-targeting degraders Preclinical Potentially selective for mutant p53 forms [ 166 ] Bypass Apoptosis induction BH3 mimetics (venetoclax/navitoclax) Approved/clinical p53-independent killing of primed tumors [ 209 - 211 ] Exploit Checkpoint inhibition WEE1 (adavosertib), CHK1/ATR inhibitors Clinical Most effective in p53-deficient contexts under replication stress. [ 174 - 179 ] Immune Neoantigen targeting Mutant p53 vaccines/TCRs Early clinical trials Patient-specific design; HLA constraints [ 127 ]

TP53 mutations and immunotherapy responses

Emerging evidence shows that TP53 mutations can significantly influence responses to immunotherapy, highlighting their growing clinical importance [ 125 – 127 ]. Mutant p53 affects tumor immunogenicity through various mechanisms, including altered apoptosis, changes in the tumor microenvironment, and modulation of immune checkpoint pathways [ 127 – 129 ]. While TP53 -driven genomic instability can increase neoantigen burden and enhance responsiveness to immune checkpoint inhibitors in certain contexts [ 130 ], mutant p53 can also promote immunosuppressive signaling and immune evasion [ 128 , 129 ]. Notably, recent studies in non-small cell lung cancer indicate that TP53 mutations can have varying effects on immunotherapy outcomes, depending on co-occurring oncogenic alterations. This underscores the context-dependent nature of these interactions [ 125 , 126 ].

Prognostic and translational implications of TP53 mutations

TP53 mutations remain among the strongest prognostic biomarkers in oncology, consistently associated with poor survival and reduced treatment efficacy [ 4 , 131 , 132 ]. In addition to their prognostic significance, translational studies and clinical trials increasingly consider TP53 status to stratify patients and guide therapeutic development [ 4 , 133 ]. Recent trials in solid tumors and hematologic malignancies highlight both the limitations of TP53 as a predictive biomarker for standard therapies and its growing relevance for emerging p53-directed strategies [ 35 , 134 ]. Basket trials targeting specific TP53 mutations, such as Y220C-selective reactivators, exemplify a shift toward mutation-informed trial design and precision oncology approaches [ 135 – 137 ]. These findings position TP53 mutations as both mechanistic drivers and clinically actionable biomarkers for prognosis and therapeutic response.

Restoring the guardian: strategies to target mutant p53

Given the high occurrence of TP53 mutations in cancer and their significant effect on treatment responses, restoring or reactivating p53 function has become a key objective in translational oncology. Unlike other tumor suppressors, mutant p53 is often stably expressed and accumulates in cancer cells. This presents both a challenge and an opportunity: it is a challenge because conventional therapies can fail when p53 is absent; however, it also presents an opportunity because the protein is present, can be targeted with drugs, and is associated with vulnerabilities specific to cancer. Researchers have developed multiple strategies to restore wild-type p53 function, eliminate mutant protein, or target downstream pathways. These approaches are changing how clinicians and researchers perceive mutant p53—not just as a loss of function but as a potential therapeutic target.

Gene therapy approaches

One of the earliest strategies to restore p53 activity was gene therapy, which aimed to reintroduce wild-type TP53 into tumor cells. (1) Viral vector delivery. Adenoviral constructs encoding the wild-type p53 protein, such as Gendicine in China [ 139 ] and Advexin in the U.S [ 140 ]., were developed in the 1990s and 2000s. Gendicine, the world’s first approved gene therapy, was approved in 2003 for the treatment of HNSCC [ 138 – 140 ]. Clinical results revealed improved responses to radiotherapy and better survival rates. Nonetheless, challenges such as limited transduction efficiency, immune responses, and transient expression have hampered its broader application. Some engineered adenoviruses selectively replicate in p53-deficient cells (e.g., ONYX-015) [ 141 ]. ONYX-015 (dl1520) was an early, extensively studied oncolytic adenovirus that lacked the E1B-55 K gene and was designed to replicate selectively in p53-deficient cancer cells. It showed some activity in HNSCC and other tumors [ 142 ]. (2) Next-generation approaches. Recent advances in nanoparticle delivery [ 143 ] and CRISPR/ Cas9 editing [ 144 , 145 ] are reigniting interest in p53 gene therapy. CRISPR-based strategies enable direct correction of hotspot mutations, although challenges related to specificity and delivery remain. Gene therapy has demonstrated that reactivating p53 pathways is both feasible and therapeutically relevant.

Reactivation of wild-type p53 via MDM2 inhibition

In tumors retaining wild-type TP53 , pharmacologic inhibition of MDM2 represents a direct strategy to restore p53 tumor suppressor activity. Small-molecule MDM2 inhibitors, including Nutlin-3, RG7112, and the clinical-grade inhibitor navtemadlin (KRT-232), disrupt the p53–MDM2 interaction, preventing p53 ubiquitination and degradation [ 146 – 150 ]. This leads to p53 stabilization and activation of transcriptional programs governing cell cycle arrest and apoptosis. Navtemadlin (KRT-232) is an oral MDM2 inhibitor that reactivates p53 in TP53 wild-type myelofibrosis cells. In the Phase III BOREAS study ( NCT03662126 ), navtemadlin monotherapy demonstrated significant efficacy compared to the best available therapy in JAK-inhibitor relapsed or refractory myelofibrosis, improving spleen volume, symptom burden, and biomarkers of disease modification [ 146 , 147 ]. However, p53 turnover is regulated by a network of E3 ligases, including Pirh2 [ 94 ] and UBE4B [ 8 ], highlighting the complexity of sustaining p53 activation and the challenges associated with targeting this pathway long-term. More recently, we have shown that the SWIB/MDM2 motif of UBE4B is critical for activating the p53 pathway, highlighting the intricate protein-protein interactions that fine-tune p53 stability [ 6 ]. This complexity underscores why targeting the central p53-MDM2 interaction remains an attractive, albeit challenging, therapeutic strategy. Nutlins were among the first potent and selective small-molecule MDM2 inhibitors [ 148 , 149 ]. Nutlins are designed to bind to MDM2, thereby blocking its interaction with p53. This inhibition prevents p53 degradation, leading to its accumulation and activation of tumor suppressor functions, such as cell cycle arrest and apoptosis, in cancer cells with wild-type p53 [ 148 , 149 , 151 , 152 ]. A more advanced MDM2 inhibitor, Idasanutlin (RG7388), has undergone testing in clinical trials, especially for acute myeloid leukemia (AML) with wild-type p53 [ 153 ].

Targeting mutant p53 for degradation

Targeting mutant p53 has long been seen as a primary goal in cancer therapy. Historically, it seemed challenging due to p53’s role as a transcription factor and the diverse mutations in the TP53 gene. However, advancements in p53 biology and drug discovery are making it increasingly feasible to target mutant p53 therapeutically.

Diverse strategies are being developed to target mutant p53, ranging from restoring its wild-type function to promoting its degradation or inhibiting its oncogenic activities.

(1) Reactivation/Restoration of wild-type-like conformation. Many common missense mutations in p53, especially those that affect its conformation, result in misfolding and destabilization, particularly in the DNA-binding domain. This approach uses small molecules that bind to the mutant p53 protein, thereby facilitating its refolding into a functional conformation similar to that of the wild-type protein. Once properly folded, the p53 protein can bind to DNA and activate its target genes. For example, (a) APR-246 (eprenetapopt). This prodrug is converted to methylene quinuclidinone (MQ), which binds to mutant p53 and targets cysteine residues, thereby restoring its function. It has shown promising results in clinical trials for TP53 -mutated MDS and AML [ 154 ]. (b) PC14586 (rezatapopt). A highly specific small molecule designed to reactivate the TP53 Y220C mutant. It binds to a specific pocket created by the Y220C mutation, stabilizing the protein and restoring its wild-type function. It has shown early clinical activity in solid tumor basket trials [ 155 ]. (c) COTI-2 is a small molecule demonstrating efficacy in preclinical models and early clinical trials for TP53 -mutated cancers, believed to reactivate mutant p53 [ 156 ]. (d) p53 requires zinc for proper folding. Compounds such as zinc metallochaperones (e.g., ZMC1) restore zinc coordination to misfolded mutants, rescuing DNA-binding function [ 157 ]. Preclinical models show strong antitumor effects, especially in R175H mutants.

(2) Degradation of mutant p53. This strategy aims to eliminate the harmful mutant p53 protein found in cancer cells. Mutant p53 often accumulates to high levels due to its increased stability and resistance to degradation. Approaches include: (a) HSP90 inhibitors : Heat shock protein 90 (HSP90) is a molecular chaperone that assists in the proper folding and stability of numerous client proteins, including many that are oncogenic. HSP90 often stabilizes misfolded mutant p53. Inhibiting HSP90 can lead to the degradation of mutant p53 [ 158 , 159 ]. Ganetespib, an HSP90 inhibitor, has been shown in preclinical studies to inhibit HSP90, thereby decreasing mutant p53 levels in various cancer cell lines and restoring sensitivity to apoptosis [ 160 , 161 ]. (b) HDAC inhibitors. Histone deacetylase (HDAC) inhibitors are a class of drugs that block the activity of HDAC enzymes, which are involved in removing acetyl groups from histones and other proteins. This leads to increased acetylation, primarily affecting chromatin structure and gene expression. However, HDAC inhibitors can also affect the stability and degradation of non-histone proteins, including p53. Some studies suggest that HDAC inhibitors can induce the acetylation of mutant p53, which may target it for degradation or alter the expression of chaperones and proteasomal components involved in the turnover of mutant p53. Their effect on mutant p53 is often indirect and context-dependent [ 162 , 163 ]. Vorinostat (SAHA), Panobinostat, and Romidepsin are FDA-approved HDAC inhibitors. While their primary action is on chromatin, they have been observed to modulate the stability of mutant p53 in some cancer models [ 164 – 166 ]. (c) Proteolysis-targeting chimeras (PROTACs) are groundbreaking bifunctional small molecules designed to induce the targeted degradation of specific proteins [ 167 ]. A PROTAC molecule typically consists of three parts: a ligand that binds to the target protein (e.g., mutant p53), a ligand that binds to an E3 ubiquitin ligase, and a linker connecting the two. By bringing mutant p53 into close proximity with an E3 ligase, the PROTAC forces the ubiquitination of mutant p53, marking it for rapid and efficient degradation by the proteasome. This offers high specificity and the potential for catalytic degradation (a single PROTAC molecule can induce the degradation of multiple target proteins). While a clinically approved PROTAC specifically targeting mutant p53 is still in development, this technology represents one of the most exciting avenues. Proof-of-concept studies are underway, demonstrating the feasibility of designing PROTACs to degrade mutant p53 isoforms. The challenge lies in finding suitable “binder” molecules that can selectively engage different mutant p53 conformations [ 167 ]. (d) Autophagy modulators. Autophagy (“self-eating”) is a lysosomal degradation pathway responsible for clearing damaged organelles, protein aggregates, and other cellular components. Mutant p53 proteins, especially those that misfold and aggregate, can sometimes be cleared through the autophagy-lysosome pathway. However, the role of autophagy in mutant p53 degradation is complex and context-dependent. Autophagy inducers, such as resveratrol and rapamycin, have been explored in preclinical studies for their potential to reduce mutant p53 levels [ 168 , 169 ]. Conversely, autophagy inhibitors such as chloroquine and hydroxychloroquine are being tested in cancer therapies, but their effects on mutant p53 degradation can vary significantly [ 170 , 171 ]. (e) Targeting p53 phosphorylation-dependent degradation . The stability of p53 is tightly regulated by post-translational modifications, including phosphorylation, which occurs in response to cellular stress. While phosphorylation at key sites, such as Serine 15, is known to stabilize wild-type p53, our research has uncovered a paradoxical mechanism in which the E3 ligase UBE4B specifically targets p53 phosphorylated at Serines 15 and 392 for degradation [ 172 ]. This suggests that in certain contexts, phosphorylation can flag p53 for destruction. More recently, we have shown that phosphorylation of UBE4B itself is a key regulatory switch. DNA damage induces UBE4B phosphorylation, which in turn prevents its degradation of p53, leading to p53 accumulation and an enhanced cellular response to damage [ 173 ]. Understanding this dynamic interplay between phosphorylation and ubiquitination opens new therapeutic avenues, in which modulating the activity of kinases or ligases could be used to control the fate of both wild-type and mutant p53. Importantly, degradation-based strategies are most applicable to TP53 missense “hotspot” mutants that exhibit increased protein stability and accumulation in tumors, including R175H, R248Q/W, R273H, and R282W. These conformational and DNA-contact mutants evade efficient MDM2-mediated turnover and become highly dependent on molecular chaperones such as HSP90, thereby sustaining their oncogenic gain-of-function activities. In contrast, truncating mutations and many nonsense or frameshift variants typically produce unstable or absent p53 protein and are therefore less likely to benefit from degradation approaches.

(3) Inhibition of GOF activities. Rather than restoring wild-type p53 function, an alternative strategy aims to inhibit the oncogenic GOF activities of mutant p53. A prominent approach focuses on disrupting aberrant protein–protein interactions formed by mutant p53, particularly those involving p63 and p73. Blocking mutant p53–p63/p73 interactions has been shown to restore p63/p73 tumor suppressor functions and suppress invasion, metastasis, and survival signaling. Peptides and small molecules designed to disrupt these interactions selectively represent a promising, albeit still largely preclinical, strategy to counteract mutant p53 GOF activities [ 41 , 174 ].

Targeted degradation is appealing because it bypasses the challenge of restoring wild-type function and instead removes the oncogenic protein altogether. The therapeutic strategies aimed at targeting mutant p53 are illustrated in Fig. 4 .

Fig. 4 Therapeutic strategies targeting mutant p53. Strategies for targeting mutant p53 can be grouped into three main areas: (1) Restoration: This includes small-molecule reactivators like APR-246 and eprenetapopt, zinc metallochaperones, and CRISPR-based delivery of wild-type p53. (2) Removal: This approach focuses on destabilizing mutant p53 using HSP90 or HDAC inhibitors, PROTAC degraders, and autophagy-mediated clearance. (3) Bypassing and Exploiting Vulnerabilities: Strategies in this category target downstream dependencies or exploit synthetic lethal interactions, including BCL-2/BCL-xL inhibitors, CDK inhibitors, immune strategies, checkpoint kinase inhibitors, PARP combinations, and metabolic or proteasome targeting. These approaches highlight both direct and indirect methods to counteract oncogenesis driven by mutant p53

Exploiting synthetic lethality and vulnerabilities in p53-mutant tumors

The primary advantage of this approach lies in its ability to target a compensatory pathway that p53-mutant cancer cells depend on while sparing normal cells with functional p53. This concept of synthetic lethality provides a means to eliminate cancer cells with minimal toxicity to healthy tissues.

Significant advancements have been made in this field, particularly in the areas of cell cycle checkpoint inhibitors and DNA damage repair inhibitors. ( 1) Cell cycle checkpoint inhibitors. Wild-type p53 is crucial for the G1/S and G2/M cell cycle checkpoints, which pause cell division in response to DNA damage for repair. When p53 is mutated or lost, cancer cells rely on alternative checkpoints, such as the G2/M checkpoint regulated by CHK1/2 and WEE1. Inhibiting these compensatory checkpoints forces p53-deficient cells into mitosis with unrepaired DNA, leading to cell death or mitotic catastrophe. In contrast, normal cells with functional p53 can still activate the G1/S checkpoint and tolerate damage, providing a potential therapeutic advantage. For example, (a) CHK1/CHK2 inhibitors (e.g., Adavosertib/MK-1775, Prexasertib). These agents inhibit the activity of checkpoint kinases 1 and 2 (CHK1/2), which are activated by ATR/ATM in response to DNA damage. In cells with TP53 mutations, blocking CHK1/2 results in extensive DNA damage and cell death. Adavosertib has demonstrated significant clinical activity in TP53 -mutated ovarian cancer, NSCLC, and other solid tumors, often in combination with chemotherapy, providing strong evidence of synthetic lethality. It has progressed to late-stage clinical trials [ 175 – 178 ]. (b) WEE1 inhibitors (e.g., Adarotene). WEE1 kinase is another critical regulator of the G2/M checkpoint. Inhibiting WEE1 in p53-mutant cells results in premature entry into mitosis with unrepaired DNA, leading to cell death [ 179 , 180 ]. (2) DNA damage repair (DDR) inhibitors. p53 plays a crucial role in the DNA damage response by regulating genes involved in various repair pathways. Its loss can increase cells’ reliance on specific alternative repair mechanisms. Inhibiting these compensatory pathways can lead to synthetic lethality. For example, by PARP inhibitors. (a) PARP inhibitors. PARP inhibitors are well-known for their synthetic lethality in the presence of BRCA mutations, which are defects in the homologous recombination repair pathway. However, there is an increasing understanding of how these inhibitors interact with p53 status. In certain situations, mutations in TP53 gene—especially those that result in a complete loss of p53 function—can cause cells to rely more on PARP-mediated DNA repair. This reliance makes them more sensitive to PARP inhibitors. The concept of synthetic lethality in this context can be complex and varies depending on specific circumstances [ 7 , 181 – 183 ]. (b) ATR inhibitors. ATR kinase is activated in response to replication stress and single-strand DNA breaks, coordinating subsequent repair processes. Mutations in the TP53 gene can alter a cell’s dependence on ATR, leading to synthetic lethality when ATR inhibitors are used in specific contexts, particularly when combined with agents that induce replication stress [ 184 – 186 ]. (3) Metabolic vulnerabilities. Mutant p53 has the ability to alter cellular metabolism to promote rapid growth and survival of cells. On the other hand, the loss of wild-type p53 can lead to metabolic weaknesses that can be targeted. Cells that lack p53 may become increasingly reliant on specific metabolic pathways to generate energy or maintain redox balance, for example, (a) Glutaminolysis inhibition. Some studies indicate that p53-deficient cells may rely more on glutaminolysis, a metabolic pathway that converts glutamine into essential metabolites, for growth and survival. Thus, inhibiting glutaminase (GLS) could be synthetically lethal [ 74 , 187 , 188 ]. (b) Serine/Glycine biosynthesis inhibition. p53 can regulate pathways for serine and glycine synthesis. In its absence, targeting these pathways could be synthetically lethal [ 189 ]. (4) Proteotoxic stress. Mutant p53 proteins often misfold and accumulate, which places a significant burden on the cell’s protein quality control systems, including chaperones and the proteasome. By further inhibiting these quality control systems, we can exploit this existing “proteotoxic stress” and push p53-mutant cells beyond their tolerance threshold, ultimately leading to cell death. (a) Proteasome inhibitors (e.g., Bortezomib, Carfilzomib). These drugs block the proteasome, a major protein degradation complex. While used in multiple myeloma, in other contexts, they could exacerbate proteotoxic stress in p53-mutant cells with high levels of misfolded proteins [ 190 – 192 ]. (b) HSP90 inhibitors : As mentioned previously, HSP90 inhibition leads to the degradation of mutant p53 by unmasking it for proteasomal degradation, which is a form of inducing proteotoxic stress on the cell. (5) Targeting regulatory pathways as a synthetic vulnerability . The loss of p53 function forces cancer cells to become dependent on alternative survival pathways, creating synthetic vulnerabilities. This extends to the regulatory machinery that normally controls p53. For instance, the p53/UBE4B pathway, which our lab has characterized, can be targeted to exploit this dependency. We have shown that microRNA-1301 suppresses tumor cell migration and invasion by directly targeting the p53/UBE4B pathway, demonstrating a natural regulatory mechanism that can be mimicked therapeutically [ 193 ]. Such strategies, which aim to manipulate p53 regulators, represent a novel form of synthetic lethality by pushing a deregulated system toward collapse.

Significant progress has been made in utilizing synthetic lethality for p53-mutant tumors, particularly with cell cycle checkpoint inhibitors, such as CHK1 inhibitors like Adavosertib. Clinical data demonstrate its effectiveness, particularly with DNA-damaging agents in p53-mutated cancers, such as ovarian cancer. While areas such as metabolic vulnerabilities and proteotoxic stress are promising in preclinical research, they are still lagging behind in clinical application compared to checkpoint inhibitors. The success of these strategies continues to inspire the search for new treatments. A summary of selected clinical evidence linking TP53 status to outcome is provided in Table 3 .

Table 3 Selected clinical evidence linking TP53 status to outcome (illustrative) Disease Therapy focus TP53 status considered Key finding High-grade serous ovarian cancer Platinum chemotherapy Mutant prevalent High relapse; chemoresistance common [ 26 , 118 - 120 ] AML/MDS APR-246 + azacitidine Mutant Stratified responses; mixed phase III trial outcomes [ 154 , 155 ] HNSCC Radiotherapy Mutant vs. WT Mutant predicts poorer local control [ 63 , 122 ] NSCLC Chemotherapy ± EGFR inhibitors Mutant Worse outcomes associated with TP53 mutation [ 125 , 226 , 227 ] Basket trials (MDM2 inhibitors) MDM2 blockade WT required Benefit limited to WT TP53 tumors [ 135 - 137 , 155 ]

Targeting downstream pathways of p53

The downstream pathways of p53 are an essential strategy in cancer therapy for tumors with TP53 mutations [ 2 , 194 ]. Rather than restoring mutant p53 function, this approach focuses on the consequences of p53 dysfunction [ 195 ]. It aims to exploit vulnerabilities arising from the absence of wild-type p53 or the oncogenic activities of mutant p53 by targeting genes and proteins that are abnormally regulated [ 196 , 197 ]. As illustrated in Fig. 3 , dominant-negative and gain-of-function mutant p53 activities rewire transcriptional programs and signaling pathways, providing the mechanistic basis for targeting downstream apoptotic, cell cycle, immune, and angiogenic pathways [ 198 – 200 ].

(1) Apoptotic pathways. Wild-type p53 is a powerful inducer of apoptosis, primarily by increasing the levels of pro-apoptotic BCL-2 family members, such as PUMA, NOXA, and BAX, while inhibiting anti-apoptotic proteins [ 201 – 204 ]. When p53 is mutated, cells lose this essential trigger for apoptosis, allowing survival despite damage or stress [ 205 ].

To restore programmed cell death, strategies include direct activation of pro-apoptotic pathways or inhibition of anti-apoptotic proteins [ 206 ]. (a) BH3 mimetics (e.g. , Venetoclax) inhibit anti-apoptotic BCL-2 family members and release pro-apoptotic proteins, triggering apoptosis independently of p53 [ 207 , 208 ]. Venetoclax is effective in leukemias such as CLL, where TP53 mutations are a major risk factor [ 209 – 211 ]. (b) TRAIL receptor agonists activate extrinsic apoptotic signaling and can bypass upstream defects, including p53 loss [ 212 – 214 ].

(2) Cell cycle regulators. Wild-type p53 induces cell cycle arrest primarily through transcriptional activation of CDKN1A/p21 [ 215 , 216 ]. Loss of this checkpoint in p53-mutant cells promotes unchecked proliferation and genomic instability [ 217 , 218 ]. CDK4/6 inhibitors block G1 progression and can induce arrest or senescence in p53-deficient contexts [ 219 , 220 ]. While most effective in HR+/HER2 − breast cancer, altered cell-cycle dependencies in TP53 -mutant tumors are under investigation [ 221 , 222 ].

(3) Immune modulation. Mutant p53 influences the tumor microenvironment by increasing genomic instability and neoantigen load, while also promoting immunosuppression via PD-L1 upregulation and recruitment of myeloid-derived suppressor cells [ 223 – 225 ]. Immune checkpoint inhibitors (ICIs) may be effective in TP53 -mutated tumors with high tumor mutational burden, such as NSCLC [ 125 , 226 , 227 ]. However, specific GOF p53 mutants can also drive immune evasion, suggesting the need for combination strategies [ 228 – 230 ].

(4) Angiogenesis inhibitors. Wild-type p53 suppresses angiogenesis by inducing anti-angiogenic factors such as thrombospondin-1 and repressing VEGF [ 231 – 233 ]. In contrast, GOF p53 mutants can promote angiogenesis and metastasis [ 231 , 234 , 235 ]. VEGF/VEGFR inhibitors, including bevacizumab and multi-kinase inhibitors, may therefore be particularly relevant in tumors where mutant p53 drives angiogenic signaling [ 236 – 238 ].

By understanding the specific downstream effects of p53 dysfunction across tumor types, researchers and clinicians can strategically leverage existing targeted therapies or develop new ones to treat p53-mutant cancers effectively. This approach often serves as the foundation for personalized and combination therapies. The key pathways targeted by p53 and the corresponding therapeutic strategies are summarized in Table 4 .

Table 4 Key p53 target pathways and associated therapeutic strategies Function Representative p53 target genes Therapeutic leverage Cell-cycle arrest CDKN1A (p21) CDK inhibitors show synergy with p53 loss or mutation [ 215 , 216 ]. DNA repair GADD45, DDB2, XPC PARP, ATR, and CHK1 inhibitors in combination therapies [ 175 - 186 ]. Apoptosis BAX, PUMA, NOXA, FAS BH3 mimetics; death receptor agonists [ 198 , 201 - 204 ]. Senescence PAI-1, IGFBP3 Senolytics are explored in specific contexts [ 30 , 219 , 220 ]. Metabolism TIGAR, SCO2, GLS2 Metabolic inhibitors (e.g., targeting OXPHOS or glycolysis) [ 73 - 75 ]. Angiogenesis TSP1, repression of VEGFA Anti-VEGF synergy varies with p53 status [ 236 - 238 ]. Immune modulation STING axis components, MHC Class I regulators Immune checkpoint blockade; therapeutic vaccines [ 127 ].

The future of p53-targeted cancer therapy

Few molecules in cancer biology have garnered as much attention as p53. Originally identified as a viral oncoprotein-binding partner, p53 has since been recognized as the most frequently mutated tumor suppressor gene. This has positioned it at the center of decades of research. However, despite extensive efforts, there is currently no universally effective therapy that directly targets p53 in clinical practice. The future of p53-targeted therapy will depend on integrating insights from structural biology, drug development, and clinical oncology with the precision tools of modern medicine.

Personalized medicine and p53 mutational status

Personalized medicine, also known as precision medicine, is an approach to patient care that customizes medical decisions, treatments, practices, or products for each individual based on their predicted response or risk of disease [ 4 , 131 ]. In oncology, this often involves using the unique molecular profile of a tumor, including the mutational status of the TP53 gene, to guide treatment choices [ 239 ]. TP53 is the most commonly mutated gene in human cancer [ 131 , 240 ], making it a key factor in developing personalized medicine strategies.

Understanding the p53 status of a tumor is essential for clinicians because it allows them to stratify risk and prognosis. TP53 mutations are often associated with more aggressive disease, higher rates of recurrence, and decreased overall survival in various types of cancer, including chronic lymphocytic leukemia (CLL), breast cancer, and glioblastoma [ 63 , 132 , 196 , 241 ]. Therefore, identifying these mutations is crucial for assessing risk, and it may warrant more intensive monitoring or a more aggressive initial treatment approach [ 242 ]. The presence or absence of functional p53 can significantly influence a tumor’s response to therapy [ 149 ], including: (a) Chemotherapy and radiotherapy. Many conventional DNA-damaging agents rely on wild-type p53 to induce apoptosis [ 241 , 242 ]. Consequently, TP53 -mutated tumors often exhibit resistance to chemotherapy and radiation, necessitating alternative therapeutic strategies. (b) Targeted agents. In tumors retaining wild-type p53 but exhibiting p53 inactivation due to MDM2 overexpression, MDM2 inhibitors represent a rational, personalized approach [ 148 , 149 ]. In contrast, tumors harboring specific TP53 missense mutations (e.g., Y220C) may benefit from mutation-specific reactivators, such as PC14586 [ 136 , 243 ]. (c) Immunotherapy. In some tumor contexts, particularly non–small cell lung cancer, TP53 mutations correlate with higher tumor mutational burden and improved responses to immune checkpoint inhibitors [ 223 , 225 , 244 ], thereby informing patient selection for immunotherapy. (d) Synthetic lethality. Targeting synthetic lethal interactions in p53-deficient cells, such as inhibition of CHK1/CHK2 or other DNA damage response components, exploits vulnerabilities that arise specifically from loss of p53 function [ 245 – 247 ]. In addition, patients with defined TP53 mutations are frequently selected for enrollment in clinical trials evaluating novel p53-directed therapies, including mutant p53 reactivators, degraders, and PROTAC-based approaches [ 154 , 167 ]. Future clinical practice will likely incorporate routine TP53 sequencing as a biomarker for therapy selection [ 126 ]. Customized therapeutic strategies—such as mutation-specific reactivation or targeted degradation—may be matched to individual patient genotypes [ 126 , 167 ]. In addition, p53 status may inform the design of rational combination therapies, including immune checkpoint blockade or metabolic modulation, to exploit p53-dependent vulnerabilities [ 35 ].

Challenges and limitations in targeting p53

Despite the significant potential of targeting p53 in therapies and incorporating TP53 status into personalized medicine, considerable challenges remain [ 248 ].

(1) The wide range of TP53 alterations, from missense mutations that affect DNA binding to null mutations, complicates the development of universal therapies. This diversity often requires the creation of mutation-specific drugs, such as structure-correctors for the Y220C mutation, along with precise biomarker-driven patient stratification [ 11 , 62 ].

(2) The biological effects of p53 mutations can differ significantly depending on the tissue type and genetic background, a phenomenon known as “context dependence.” A treatment that works well in one tissue type may be ineffective in another due to overlapping signaling pathways or different downstream effectors. This variability makes it challenging to predict therapeutic responses [ 195 ].

(3) Small molecules, gene therapy vectors, and nanoparticle-based delivery systems face challenges related to stability, selectivity, and off-target toxicity. For example, viral vectors often induce immunogenicity, while small molecules targeting protein-protein interactions (like MDM2 inhibitors) have been hampered by dose-limiting hematological toxicities [ 249 , 250 ].

(4) As with many targeted therapies, tumors can acquire compensatory or bypass mechanisms that diminish the durability of p53-directed treatments. Mechanisms include the upregulation of downstream anti-apoptotic factors (e.g., MCL-1) or the emergence of secondary mutations that prevent drug binding [ 251 ].

(5) Many p53-targeting agents have historically been evaluated in late-stage, heavily pretreated patients with complex genomic landscapes. This approach may underestimate the true therapeutic potential of these drugs, suggesting that earlier intervention strategies or specific combination settings are required to reveal meaningful clinical benefit [ 35 , 248 ]. Addressing these challenges will require continued innovation in drug design, improved biomarker integration, and more efficient clinical trial frameworks [ 35 ].

Ongoing research and novel therapies

Despite these challenges, the future of personalized medicine based on TP53 mutational status remains promising and will likely require a multifaceted approach [ 250 ].

(1) Efforts are ongoing to develop more potent, selective, and orally bioavailable compounds that reactivate specific mutant p53 conformations (e.g., PC14586 for the Y220C mutation) or induce degradation of mutant p53 through PROTAC-based strategies [ 167 , 252 ]. Clinical progress with agents such as APR-246 (eprenetapopt) and the specific Y220C reactivator has validated these concepts, showing promise in early-phase trials [ 154 , 155 ].

(2) Combining p53-targeting agents with chemotherapy, radiotherapy, targeted therapies, or immunotherapy may enhance efficacy and overcome resistance. For instance, restoring p53 function can sensitize tumors to immune checkpoint blockade by remodeling the tumor microenvironment [ 253 , 254 ].

(3) CRISPR-based gene editing technologies offer the potential for precise correction of TP53 mutations. While preclinical models have demonstrated feasibility, challenges related to delivery efficiency, off-target effects, and safety remain substantial obstacles to clinical translation [ 255 , 256 ].

(4) Identifying and clinically translating synthetic lethal interactions in p53-mutant cancers—such as targeting the G2/M checkpoint via WEE1 or CHK1 inhibitors—represents a major therapeutic opportunity [ 257 , 258 ].

(5) Artificial intelligence and deep learning tools, such as AlphaFold, are increasingly used to predict the 3D structures of specific p53 mutants, identify novel druggable pockets, and guide rational drug design [ 259 , 260 ].

(6) Routine, cost-effective genomic profiling will facilitate precise identification of TP53 mutation types and co-mutations, enabling more informed, personalized treatment decisions [ 261 , 262 ]. Figure 5 illustrates a precision medicine framework targeting p53 in cancer therapy.

Fig. 5 Precision medicine framework for targeting p53 in cancer. Patient tumor profiling, particularly next-generation sequencing (NGS) of the TP53 gene, is essential for shaping treatment strategies. For wild-type TP53 , therapies focus on enhancing p53 function by using MDM2 inhibitors or combining them with chemotherapy and targeted therapies. If TP53 is mutated, treatment depends on the type of mutation. Options include: (1) Reactivation with small molecules (like APR-246) and stabilizers. (2) Removal through HSP90/HDAC inhibition or PROTAC degraders. (3) Exploiting vulnerabilities using BH3 mimetics, checkpoint inhibitors, or immunotherapy. These approaches ultimately aim to combine therapies and encourage participation in clinical trials to improve patient outcomes

Conclusion and future perspectives

The tumor suppressor p53 remains one of the most critical guardians of genomic stability, and its frequent mutation across cancers underscores its central role in tumorigenesis [ 3 , 239 ]. Mutant p53 not only disables canonical tumor-suppressive pathways but also exerts dominant-negative and gain-of-function effects that promote cancer progression and therapeutic resistance [ 51 , 196 ]. These alterations complicate responses to conventional therapies while shaping sensitivity to emerging targeted and immunotherapeutic approaches [ 128 , 263 ].

p53 mutations offer opportunities for therapeutic innovation, including gene therapy, small-molecule reactivation, targeted degradation, and strategies based on synthetic lethality [ 35 , 195 , 258 ]. The rapid evolution of technologies such as CRISPR editing, PROTACs, and precision drug design suggests that effective p53-targeted therapies may soon become clinically feasible [ 167 , 250 , 264 ].

Ultimately, successful p53-targeted therapy will depend not only on targeting the mutant protein itself but also on understanding the broader regulatory networks governing p53 stability and function. The ubiquitin–proteasome system represents a critical hub of vulnerability, and modulating key E3 ligases or stress-response pathways offers a promising—albeit complex—therapeutic window [ 265 – 267 ]. This systems-level view of the p53 pathway provides fertile ground for continued therapeutic innovation.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

We appreciate all members of our research team for their invaluable contributions, constructive feedback, and insightful suggestions.

Author contributions

HHW drafted the manuscript. SL, CS, DDE discussed and provided support for the manuscript. RL supervised the study. HHW and RL revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by grants from the Women & Children’s Health Research Institute (WCHRI) and the Canadian Institutes of Health Research (CIHR, PLL-192128) to RL.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read and approved the final version of the manuscript and its publication.

Competing interests

The authors declare no competing interests.

References

1. Levine AJ p53, the cellular gatekeeper for growth and division Cell 1997 88 323 31 10.1016/S0092-8674(00)81871-1 9039259 Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–31. 9039259 10.1016/s0092-8674(00)81871-1

2. Levine AJ Oren M The first 30 years of p53: growing ever more complex Nat Rev Cancer 2009 9 749 58 10.1038/nrc2723 19776744 PMC2771725 Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–58. 19776744 10.1038/nrc2723 PMC2771725

3. Vogelstein B Lane D Levine AJ Surfing the p53 network Nature 2000 408 307 10 10.1038/35042675 11099028 Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10. 11099028 10.1038/35042675

4. Olivier M Hollstein M Hainaut P TP53 mutations in human cancers: origins, consequences, and clinical use Cold Spring Harb Perspect Biol 2010 2 a001008 10.1101/cshperspect.a001008 20182602 PMC2827900 Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008. 20182602 10.1101/cshperspect.a001008 PMC2827900

5. Chen X Zhang T Su W Dou Z Zhao D Jin X Mutant p53 in cancer: from molecular mechanism to therapeutic modulation Cell Death Dis 2022 13 974 10.1038/s41419-022-05408-1 36400749 PMC9674619 Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X, et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 2022;13:974. 36400749 10.1038/s41419-022-05408-1 PMC9674619

6. Wu HH Leng S Abuetabh Y Sergi C Eisenstat DD Leng R The SWIB/MDM2 motif of UBE4B activates the p53 pathway Mol Ther Nucleic Acids 2023 31 466 81 10.1016/j.omtn.2023.02.002 36865087 PMC9971181 Wu HH, Leng S, Abuetabh Y, Sergi C, Eisenstat DD, Leng R. The SWIB/MDM2 motif of UBE4B activates the p53 pathway. Mol Ther Nucleic Acids. 2023;31:466–81. 36865087 10.1016/j.omtn.2023.02.002 PMC9971181

7. Abuetabh Y Wu HH Chai C Al Yousef H Persad S Sergi CM DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities Exp Mol Med 2022 54 1658 69 10.1038/s12276-022-00863-4 36207426 PMC9636249 Abuetabh Y, Wu HH, Chai C, Al Yousef H, Persad S, Sergi CM, et al. DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities. Exp Mol Med. 2022;54:1658–69. 36207426 10.1038/s12276-022-00863-4 PMC9636249

8. Wu H Pomeroy SL Ferreira M Teider N Mariani J Nakayama KI UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53 Nat Med 2011 17 347 55 10.1038/nm.2283 21317885 Wu H, Pomeroy SL, Ferreira M, Teider N, Mariani J, Nakayama KI, et al. UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53. Nat Med. 2011;17:347–55. 21317885 10.1038/nm.2283

9. Joerger AC Stiewe T Soussi T TP53: the unluckiest of genes? Cell Death Differ 2025 32 219 24 10.1038/s41418-024-01391-6 39443700 PMC11803090 Joerger AC, Stiewe T, Soussi T. TP53: the unluckiest of genes? Cell Death Differ. 2025;32:219–24. 39443700 10.1038/s41418-024-01391-6 PMC11803090

10. Freed-Pastor WA Prives C Mutant p53: one name, many proteins Genes Dev 2012 26 1268 86 10.1101/gad.190678.112 22713868 PMC3387655 Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26:1268–86. 22713868 10.1101/gad.190678.112 PMC3387655

11. Baugh EH Ke H Levine AJ Bonneau RA Chan CS Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 2018 25 154 60 10.1038/cdd.2017.180 29099487 PMC5729536 Baugh EH, Ke H, Levine AJ, Bonneau RA, Chan CS. Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ. 2018;25:154–60. 29099487 10.1038/cdd.2017.180 PMC5729536

12. Boettcher S Miller PG Sharma R McConkey M Leventhal M Krivtsov AV A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies Science 2019 365 599 604 10.1126/science.aax3649 31395785 PMC7327437 Boettcher S, Miller PG, Sharma R, McConkey M, Leventhal M, Krivtsov AV, et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science. 2019;365:599–604. 31395785 10.1126/science.aax3649 PMC7327437

13. Hoyos D Greenbaum B Levine AJ The genotypes and phenotypes of missense mutations in the proline domain of the p53 protein Cell Death Differ 2022 29 938 45 10.1038/s41418-022-00980-7 35383292 PMC9090814 Hoyos D, Greenbaum B, Levine AJ. The genotypes and phenotypes of missense mutations in the proline domain of the p53 protein. Cell Death Differ. 2022;29:938–45. 35383292 10.1038/s41418-022-00980-7 PMC9090814

14. Kato S Han SY Liu W Otsuka K Shibata H Kanamaru R Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis Proc Natl Acad Sci U S A 2003 100 8424 9 10.1073/pnas.1431692100 12826609 PMC166245 Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A. 2003;100:8424–9. 12826609 10.1073/pnas.1431692100 PMC166245

15. Klemm N Schimmer RR Konrad NK Thelen F Fullin J Topcu E The Prolonged Half-Life of the p53 Missense Variant R248Q Promotes Accumulation and Heterotetramer Formation with Wild-Type p53 to Exert the Dominant-Negative Effect Cancer Res 2025 85 1978 96 10.1158/0008-5472.CAN-24-1136 40163352 PMC12127799 Klemm N, Schimmer RR, Konrad NK, Thelen F, Fullin J, Topcu E, et al. The Prolonged Half-Life of the p53 Missense Variant R248Q Promotes Accumulation and Heterotetramer Formation with Wild-Type p53 to Exert the Dominant-Negative Effect. Cancer Res. 2025;85:1978–96. 40163352 10.1158/0008-5472.CAN-24-1136 PMC12127799

16. Chiang YT, Chien YC, Lin YH, Wu HH, Lee DF, Yu YL. The Function of the Mutant p53-R175H in Cancer. Cancers (Basel) 2021;13. 10.3390/cancers13164088 PMC8391618 34439241

17. Lepre MG, Omar SI, Grasso G, Morbiducci U, Deriu MA, Tuszynski JA. Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA. Molecules 2017;22. 10.3390/molecules22081358 PMC6152093 28813011

18. Nakazawa S Sakata KI Liang S Yoshikawa K Iizasa H Tada M Dominant-negative p53 mutant R248Q increases the motile and invasive activities of oral squamous cell carcinoma cells Biomed Res 2019 40 37 49 10.2220/biomedres.40.37 30787262 Nakazawa S, Sakata KI, Liang S, Yoshikawa K, Iizasa H, Tada M, et al. Dominant-negative p53 mutant R248Q increases the motile and invasive activities of oral squamous cell carcinoma cells. Biomed Res. 2019;40:37–49. 30787262 10.2220/biomedres.40.37

19. Wang H Liao P Zeng SX Lu H It takes a team: a gain-of-function story of p53-R249S J Mol Cell Biol 2019 11 277 83 10.1093/jmcb/mjy086 30608603 PMC6487778 Wang H, Liao P, Zeng SX, Lu H. It takes a team: a gain-of-function story of p53-R249S. J Mol Cell Biol. 2019;11:277–83. 30608603 10.1093/jmcb/mjy086 PMC6487778

20. Lundine D Annor GK Chavez V Maimos S Syed Z Jiang S The C-terminus of Gain-of-Function Mutant p53 R273H Is Required for Association with PARP1 and Poly-ADP-Ribose Mol Cancer Res 2022 20 1799 810 10.1158/1541-7786.MCR-22-0133 36074101 PMC9716242 Lundine D, Annor GK, Chavez V, Maimos S, Syed Z, Jiang S, et al. The C-terminus of Gain-of-Function Mutant p53 R273H Is Required for Association with PARP1 and Poly-ADP-Ribose. Mol Cancer Res. 2022;20:1799–810. 36074101 10.1158/1541-7786.MCR-22-0133 PMC9716242

21. Zhang Y Coillie SV Fang JY Xu J Gain of function of mutant p53: R282W on the peak? Oncogenesis 2016 5 e196 10.1038/oncsis.2016.8 26878390 PMC5154345 Zhang Y, Coillie SV, Fang JY, Xu J. Gain of function of mutant p53: R282W on the peak? Oncogenesis. 2016;5:e196. 26878390 10.1038/oncsis.2016.8 PMC5154345

22. Palomar-Siles M Heldin A Zhang M Strandgren C Yurevych V van Dinter JT Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine Cell Death Dis 2022 13 997 10.1038/s41419-022-05431-2 36433934 PMC9700717 Palomar-Siles M, Heldin A, Zhang M, Strandgren C, Yurevych V, van Dinter JT, et al. Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine. Cell Death Dis. 2022;13:997. 36433934 10.1038/s41419-022-05431-2 PMC9700717

23. Holmfeldt L Wei L Diaz-Flores E Walsh M Zhang J Ding L The genomic landscape of hypodiploid acute lymphoblastic leukemia Nat Genet 2013 45 242 52 10.1038/ng.2532 23334668 PMC3919793 Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242–52. 23334668 10.1038/ng.2532 PMC3919793

24. Zerdoumi Y Lanos R Raad S Flaman JM Bougeard G Frebourg T Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage Hum Mol Genet 2017 26 2812 10.1093/hmg/ddx165 28472496 PMC5886279 Zerdoumi Y, Lanos R, Raad S, Flaman JM, Bougeard G, Frebourg T, et al. Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. Hum Mol Genet. 2017;26:2812. 28472496 10.1093/hmg/ddx165 PMC5886279

25. Tong DR Zhou W Katz C Regunath K Venkatesh D Ihuegbu C p53 Frameshift Mutations Couple Loss-of-Function with Unique Neomorphic Activities Mol Cancer Res 2021 19 1522 33 10.1158/1541-7786.MCR-20-0691 34045312 PMC8419077 Tong DR, Zhou W, Katz C, Regunath K, Venkatesh D, Ihuegbu C, et al. p53 Frameshift Mutations Couple Loss-of-Function with Unique Neomorphic Activities. Mol Cancer Res. 2021;19:1522–33. 34045312 10.1158/1541-7786.MCR-20-0691 PMC8419077

26. Garziera M, Cecchin E, Giorda G, Sorio R, Scalone S, De Mattia E et al. Clonal Evolution of TP53 c.375 + 1G > A Mutation in Pre- and Post- Neo-Adjuvant Chemotherapy (NACT) Tumor Samples in High-Grade Serous Ovarian Cancer (HGSOC). Cells 2019;8. 10.3390/cells8101186 PMC6829309 31581548

27. Hettmer S Archer NM Somers GR Novokmet A Wagers AJ Diller L Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers Cancer 2014 120 1068 75 10.1002/cncr.28507 24382691 PMC4173134 Hettmer S, Archer NM, Somers GR, Novokmet A, Wagers AJ, Diller L, et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer. 2014;120:1068–75. 24382691 10.1002/cncr.28507 PMC4173134

28. Chen M Chen X Li S Pan X Gong Y Zheng J An Epigenetic Mechanism Underlying Chromosome 17p Deletion-Driven Tumorigenesis Cancer Discov 2021 11 194 207 10.1158/2159-8290.CD-20-0336 32978226 PMC8591992 Chen M, Chen X, Li S, Pan X, Gong Y, Zheng J, et al. An Epigenetic Mechanism Underlying Chromosome 17p Deletion-Driven Tumorigenesis. Cancer Discov. 2021;11:194–207. 32978226 10.1158/2159-8290.CD-20-0336 PMC8591992

29. Levine AJ Spontaneous and inherited TP53 genetic alterations Oncogene 2021 40 5975 83 10.1038/s41388-021-01991-3 34389799 PMC8516647 Levine AJ. Spontaneous and inherited TP53 genetic alterations. Oncogene. 2021;40:5975–83. 34389799 10.1038/s41388-021-01991-3 PMC8516647

30. Amadou A Achatz MIW Hainaut P Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome Curr Opin Oncol 2018 30 23 9 10.1097/CCO.0000000000000423 29076966 Amadou A, Achatz MIW, Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. Curr Opin Oncol. 2018;30:23–9. 29076966 10.1097/CCO.0000000000000423

31. Bougeard G Renaux-Petel M Flaman JM Charbonnier C Fermey P Belotti M Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers J Clin Oncol 2015 33 2345 52 10.1200/JCO.2014.59.5728 26014290 Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015;33:2345–52. 26014290 10.1200/JCO.2014.59.5728

32. Ribi S Baumhoer D Lee K Edison, Teo AS Madan B TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome Oncotarget 2015 6 7727 40 10.18632/oncotarget.3115 25762628 PMC4480712 Ribi S, Baumhoer D, Lee K, Edison, Teo AS, Madan B, et al. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome. Oncotarget. 2015;6:7727–40. 25762628 10.18632/oncotarget.3115 PMC4480712

33. Gannon JV Greaves R Iggo R Lane DP Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form EMBO J 1990 9 1595 602 10.1002/j.1460-2075.1990.tb08279.x 1691710 PMC551855 Gannon JV, Greaves R, Iggo R, Lane DP. Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J. 1990;9:1595–602. 1691710 10.1002/j.1460-2075.1990.tb08279.x PMC551855

34. Wang H Guo M Wei H Chen Y Targeting p53 pathways: mechanisms, structures, and advances in therapy Signal Transduct Target Ther 2023 8 92 10.1038/s41392-023-01347-1 36859359 PMC9977964 Wang H, Guo M, Wei H, Chen Y. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduct Target Ther. 2023;8:92. 36859359 10.1038/s41392-023-01347-1 PMC9977964

35. Bykov VJN Eriksson SE Bianchi J Wiman KG Targeting mutant p53 for efficient cancer therapy Nat Rev Cancer 2018 18 89 102 10.1038/nrc.2017.109 29242642 Bykov VJN, Eriksson SE, Bianchi J, Wiman KG. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 2018;18:89–102. 29242642 10.1038/nrc.2017.109

36. Cho Y Gorina S Jeffrey PD Pavletich NP Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations Science 1994 265 346 55 10.1126/science.8023157 8023157 Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994;265:346–55. 8023157 10.1126/science.8023157

37. Wang H Bao W Jiang F Che Q Chen Z Wang F Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGgamma Cancer Lett 2015 360 269 79 10.1016/j.canlet.2015.02.028 25697482 Wang H, Bao W, Jiang F, Che Q, Chen Z, Wang F, et al. Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGgamma. Cancer Lett. 2015;360:269–79. 25697482 10.1016/j.canlet.2015.02.028

38. Allende-Vega N Villalba M Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells Sci Rep 2019 9 5637 10.1038/s41598-019-42220-y 30948782 PMC6449403 Allende-Vega N, Villalba M. Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells. Sci Rep. 2019;9:5637. 30948782 10.1038/s41598-019-42220-y PMC6449403

39. Olszewski MB Pruszko M Snaar-Jagalska E Zylicz A Zylicz M Diverse and cancer type–specific roles of the p53 R248Q gain–of–function mutation in cancer migration and invasiveness Int J Oncol 2019 54 1168 82 30968154 10.3892/ijo.2019.4723 PMC6411346 Olszewski MB, Pruszko M, Snaar-Jagalska E, Zylicz A, Zylicz M. Diverse and cancer type–specific roles of the p53 R248Q gain–of–function mutation in cancer migration and invasiveness. Int J Oncol. 2019;54:1168–82. 30968154 10.3892/ijo.2019.4723 PMC6411346

40. Julian L Sang JC Wu Y Meisl G Brelstaff JH Miller A Characterization of full-length p53 aggregates and their kinetics of formation Biophys J 2022 121 4280 98 10.1016/j.bpj.2022.10.013 36230002 PMC9703098 Julian L, Sang JC, Wu Y, Meisl G, Brelstaff JH, Miller A, et al. Characterization of full-length p53 aggregates and their kinetics of formation. Biophys J. 2022;121:4280–98. 36230002 10.1016/j.bpj.2022.10.013 PMC9703098

41. Muller PA Vousden KH p53 mutations in cancer Nat Cell Biol 2013 15 2 8 10.1038/ncb2641 23263379 Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013;15:2–8. 23263379 10.1038/ncb2641

42. Tan BS Tiong KH Choo HL Chung FF Hii LW Tan SH Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF) Cell Death Dis 2015 6 e1826 10.1038/cddis.2015.191 26181206 PMC4650736 Tan BS, Tiong KH, Choo HL, Chung FF, Hii LW, Tan SH, et al. Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF). Cell Death Dis. 2015;6:e1826. 26181206 10.1038/cddis.2015.191 PMC4650736

43. Zhao Y Li Y Sheng J Wu F Li K Huang R P53-R273H mutation enhances colorectal cancer stemness through regulating specific lncRNAs J Exp Clin Cancer Res 2019 38 379 10.1186/s13046-019-1375-9 31455383 PMC6712617 Zhao Y, Li Y, Sheng J, Wu F, Li K, Huang R, et al. P53-R273H mutation enhances colorectal cancer stemness through regulating specific lncRNAs. J Exp Clin Cancer Res. 2019;38:379. 31455383 10.1186/s13046-019-1375-9 PMC6712617

44. Gencel-Augusto J Lozano G p53 tetramerization: at the center of the dominant-negative effect of mutant p53 Genes Dev 2020 34 1128 46 10.1101/gad.340976.120 32873579 PMC7462067 Gencel-Augusto J, Lozano G. p53 tetramerization: at the center of the dominant-negative effect of mutant p53. Genes Dev. 2020;34:1128–46. 32873579 10.1101/gad.340976.120 PMC7462067

45. Ly E Kugel JF Goodrich JA Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites Sci Rep 2020 10 16176 10.1038/s41598-020-73234-6 32999415 PMC7528078 Ly E, Kugel JF, Goodrich JA. Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites. Sci Rep. 2020;10:16176. 32999415 10.1038/s41598-020-73234-6 PMC7528078

46. Gaglia G Guan Y Shah JV Lahav G Activation and control of p53 tetramerization in individual living cells Proc Natl Acad Sci U S A 2013 110 15497 501 10.1073/pnas.1311126110 24006363 PMC3780836 Gaglia G, Guan Y, Shah JV, Lahav G. Activation and control of p53 tetramerization in individual living cells. Proc Natl Acad Sci U S A. 2013;110:15497–501. 24006363 10.1073/pnas.1311126110 PMC3780836

47. Jeffrey PD Gorina S Pavletich NP Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms Science 1995 267 1498 502 10.1126/science.7878469 7878469 Jeffrey PD, Gorina S, Pavletich NP. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. Science. 1995;267:1498–502. 7878469 10.1126/science.7878469

48. Willis A Jung EJ Wakefield T Chen X Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes Oncogene 2004 23 2330 8 10.1038/sj.onc.1207396 14743206 Willis A, Jung EJ, Wakefield T, Chen X. Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. Oncogene. 2004;23:2330–8. 14743206 10.1038/sj.onc.1207396

49. Stein Y Aloni-Grinstein R Rotter V Mutant p53 oncogenicity: dominant-negative or gain-of-function? Carcinogenesis 2020 41 1635 47 10.1093/carcin/bgaa117 33159515 Stein Y, Aloni-Grinstein R, Rotter V. Mutant p53 oncogenicity: dominant-negative or gain-of-function? Carcinogenesis. 2020;41:1635–47. 33159515 10.1093/carcin/bgaa117

50. Gencel-Augusto J Lozano G Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect Cancer Res 2025 85 1955 6 10.1158/0008-5472.CAN-25-1054 40452346 Gencel-Augusto J, Lozano G. Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect. Cancer Res. 2025;85:1955–6. 40452346 10.1158/0008-5472.CAN-25-1054

51. Muller PA Vousden KH Mutant p53 in cancer: new functions and therapeutic opportunities Cancer Cell 2014 25 304 17 10.1016/j.ccr.2014.01.021 24651012 PMC3970583 Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17. 24651012 10.1016/j.ccr.2014.01.021 PMC3970583

52. Yue X Zhao Y Xu Y Zheng M Feng Z Hu W Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy J Mol Biol 2017 429 1595 606 10.1016/j.jmb.2017.03.030 28390900 PMC5663274 Yue X, Zhao Y, Xu Y, Zheng M, Feng Z, Hu W. Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy. J Mol Biol. 2017;429:1595–606. 28390900 10.1016/j.jmb.2017.03.030 PMC5663274

53. Attardi LD Boutelle AM Targeting p53 gain-of-function activity in cancer therapy: a cautionary tale Cell Death Differ 2024 31 133 5 10.1038/s41418-023-01253-7 38151545 PMC10850540 Attardi LD, Boutelle AM. Targeting p53 gain-of-function activity in cancer therapy: a cautionary tale. Cell Death Differ. 2024;31:133–5. 38151545 10.1038/s41418-023-01253-7 PMC10850540

54. Schulz-Heddergott R Stark N Edmunds SJ Li J Conradi LC Bohnenberger H Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion Cancer Cell 2018 34 298 314 10.1016/j.ccell.2018.07.004 30107178 PMC6582949 Schulz-Heddergott R, Stark N, Edmunds SJ, Li J, Conradi LC, Bohnenberger H, et al. Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion. Cancer Cell. 2018;34:298–314. e297. 30107178 10.1016/j.ccell.2018.07.004 PMC6582949

55. Laptenko O Shiff I Freed-Pastor W Zupnick A Mattia M Freulich E The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain Mol Cell 2015 57 1034 46 10.1016/j.molcel.2015.02.015 25794615 PMC6221458 Laptenko O, Shiff I, Freed-Pastor W, Zupnick A, Mattia M, Freulich E, et al. The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain. Mol Cell. 2015;57:1034–46. 25794615 10.1016/j.molcel.2015.02.015 PMC6221458

56. Lane DP Cancer. p53, guardian of the genome Nature 1992 358 15 6 10.1038/358015a0 1614522 Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358:15–6. 1614522 10.1038/358015a0

57. Lane DP Mutant p53 Gain-of-Function in the Spotlight: Are We Suffering a GOF Delusion? Cancer Discov 2024 14 211 3 10.1158/2159-8290.CD-23-1362 38327191 Lane DP. Mutant p53 Gain-of-Function in the Spotlight: Are We Suffering a GOF Delusion? Cancer Discov. 2024;14:211–3. 38327191 10.1158/2159-8290.CD-23-1362

58. Zhang C Liu J Xu D Zhang T Hu W Feng Z Gain-of-function mutant p53 in cancer progression and therapy J Mol Cell Biol 2020 12 674 87 10.1093/jmcb/mjaa040 32722796 PMC7749743 Zhang C, Liu J, Xu D, Zhang T, Hu W, Feng Z. Gain-of-function mutant p53 in cancer progression and therapy. J Mol Cell Biol. 2020;12:674–87. 32722796 10.1093/jmcb/mjaa040 PMC7749743

59. Bouaoun L Sonkin D Ardin M Hollstein M Byrnes G Zavadil J TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data Hum Mutat 2016 37 865 76 10.1002/humu.23035 27328919 Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J, et al. TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data. Hum Mutat. 2016;37:865–76. 27328919 10.1002/humu.23035

60. Milner J Medcalf EA Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation Cell 1991 65 765 74 10.1016/0092-8674(91)90384-B 2040013 Milner J, Medcalf EA. Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell. 1991;65:765–74. 2040013 10.1016/0092-8674(91)90384-b

61. Brdar A, Osterburg C, Munick P, Machel AC, Rathore R, Osterburg S et al. p53 isoforms have a high aggregation propensity, interact with chaperones and lack binding to p53 interaction partners. Elife 2025;13. 10.7554/eLife.103537 PMC12422735 40928972

62. Joerger AC Fersht AR Structural biology of the tumor suppressor p53 Annu Rev Biochem 2008 77 557 82 10.1146/annurev.biochem.77.060806.091238 18410249 Joerger AC, Fersht AR. Structural biology of the tumor suppressor p53. Annu Rev Biochem. 2008;77:557–82. 18410249 10.1146/annurev.biochem.77.060806.091238

63. Brosh R Rotter V When mutants gain new powers: news from the mutant p53 field Nat Rev Cancer 2009 9 701 13 10.1038/nrc2693 19693097 Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9:701–13. 19693097 10.1038/nrc2693

64. Malkin D Li-fraumeni syndrome Genes Cancer 2011 2 475 84 10.1177/1947601911413466 21779515 PMC3135649 Malkin D. Li-fraumeni syndrome. Genes Cancer. 2011;2:475–84. 21779515 10.1177/1947601911413466 PMC3135649

65. Alvarado-Ortiz E de la Cruz-Lopez KG Becerril-Rico J Sarabia-Sanchez MA Ortiz-Sanchez E Garcia-Carranca A Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches Front Cell Dev Biol 2020 8 607670 10.3389/fcell.2020.607670 33644030 PMC7905058 Alvarado-Ortiz E, de la Cruz-Lopez KG, Becerril-Rico J, Sarabia-Sanchez MA, Ortiz-Sanchez E, Garcia-Carranca A. Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches. Front Cell Dev Biol. 2020;8:607670. 33644030 10.3389/fcell.2020.607670 PMC7905058

66. Lozano G Prives C Sabapathy K Mutant p53 Gain of Function: Why Many See It, Why Some Do Not Cancer Discov 2025 15 1099 104 10.1158/2159-8290.CD-24-1638 40287981 PMC12133405 Lozano G, Prives C, Sabapathy K. Mutant p53 Gain of Function: Why Many See It, Why Some Do Not. Cancer Discov. 2025;15:1099–104. 40287981 10.1158/2159-8290.CD-24-1638 PMC12133405

67. Cai BH, Hsu YC, Yeh FY, Lin YR, Lu RY, Yu SJ et al. P63 and P73 Activation in Cancers with p53 Mutation. Biomedicines 2022;10. 10.3390/biomedicines10071490 PMC9313412 35884795

68. Petronilho EC de Andrade GC de Sousa GDS Almeida FP Mota MF Gomes A Oncogenic p53 triggers amyloid aggregation of p63 and p73 liquid droplets Commun Chem 2024 7 207 10.1038/s42004-024-01289-x 39284933 PMC11405828 Petronilho EC, de Andrade GC, de Sousa GDS, Almeida FP, Mota MF, Gomes A, et al. Oncogenic p53 triggers amyloid aggregation of p63 and p73 liquid droplets. Commun Chem. 2024;7:207. 39284933 10.1038/s42004-024-01289-x PMC11405828

69. Zhang J Sun W Kong X Zhang Y Yang HJ Ren C Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1 Proc Natl Acad Sci U S A 2019 116 24259 67 10.1073/pnas.1913919116 31712410 PMC6883818 Zhang J, Sun W, Kong X, Zhang Y, Yang HJ, Ren C, et al. Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1. Proc Natl Acad Sci U S A. 2019;116:24259–67. 31712410 10.1073/pnas.1913919116 PMC6883818

70. Wu HH Wang B Armstrong SR Abuetabh Y Leng S Roa WHY Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and DeltaNp63 ubiquitination and degradation Nucleic Acids Res 2021 49 2740 58 10.1093/nar/gkab081 33619536 PMC7969027 Wu HH, Wang B, Armstrong SR, Abuetabh Y, Leng S, Roa WHY, et al. Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and DeltaNp63 ubiquitination and degradation. Nucleic Acids Res. 2021;49:2740–58. 33619536 10.1093/nar/gkab081 PMC7969027

71. Wang B Wu HH Abuetabh Y Leng S Davidge ST Flores ER p63, a key regulator of Ago2, links to the microRNA-144 cluster Cell Death Dis 2022 13 397 10.1038/s41419-022-04854-1 35459267 PMC9033807 Wang B, Wu HH, Abuetabh Y, Leng S, Davidge ST, Flores ER, et al. p63, a key regulator of Ago2, links to the microRNA-144 cluster. Cell Death Dis. 2022;13:397. 35459267 10.1038/s41419-022-04854-1 PMC9033807

72. Peart MJ Prives C Mutant p53 gain of function: the NF-Y connection Cancer Cell 2006 10 173 4 10.1016/j.ccr.2006.08.014 16959607 Peart MJ, Prives C. Mutant p53 gain of function: the NF-Y connection. Cancer Cell. 2006;10:173–4. 16959607 10.1016/j.ccr.2006.08.014

73. Eriksson M, Ambroise G, Ouchida AT, Lima Queiroz A, Smith D, Gimenez-Cassina A et al. Effect of Mutant p53 Proteins on Glycolysis and Mitochondrial Metabolism. Mol Cell Biol 2017;37. 10.1128/MCB.00328-17 PMC5705820 28993478

74. Liu J Zhang C Hu W Feng Z Tumor suppressor p53 and metabolism J Mol Cell Biol 2019 11 284 92 10.1093/jmcb/mjy070 30500901 PMC6487777 Liu J, Zhang C, Hu W, Feng Z. Tumor suppressor p53 and metabolism. J Mol Cell Biol. 2019;11:284–92. 30500901 10.1093/jmcb/mjy070 PMC6487777

75. Wang X Yang J Yang W Sheng H Jia B Cheng P Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m(6)A modification and diverse cell death mechanisms J Adv Res 2025 75 539 60 10.1016/j.jare.2024.10.026 39490612 PMC12789782 Wang X, Yang J, Yang W, Sheng H, Jia B, Cheng P, et al. Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m(6)A modification and diverse cell death mechanisms. J Adv Res. 2025;75:539–60. 39490612 10.1016/j.jare.2024.10.026 PMC12789782

76. Hanel W Moll UM Links between mutant p53 and genomic instability J Cell Biochem 2012 113 433 9 10.1002/jcb.23400 22006292 PMC4407809 Hanel W, Moll UM. Links between mutant p53 and genomic instability. J Cell Biochem. 2012;113:433–9. 22006292 10.1002/jcb.23400 PMC4407809

77. Hertel A, Storchova Z. The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations. Biomolecules 2025;15. 10.3390/biom15020244 PMC11852650 40001547

78. Janic A Abad E Amelio I Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control? Cell Death Differ 2025 32 1 8 10.1038/s41418-024-01259-9 38379088 PMC11742645 Janic A, Abad E, Amelio I. Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control? Cell Death Differ. 2025;32:1–8. 38379088 10.1038/s41418-024-01259-9 PMC11742645

79. Tang Q Su Z Gu W Rustgi AK Mutant p53 on the Path to Metastasis Trends Cancer 2020 6 62 73 10.1016/j.trecan.2019.11.004 31952783 PMC7485681 Tang Q, Su Z, Gu W, Rustgi AK. Mutant p53 on the Path to Metastasis. Trends Cancer. 2020;6:62–73. 31952783 10.1016/j.trecan.2019.11.004 PMC7485681

80. Muller PA Vousden KH Norman JC p53 and its mutants in tumor cell migration and invasion J Cell Biol 2011 192 209 18 10.1083/jcb.201009059 21263025 PMC3172183 Muller PA, Vousden KH, Norman JC. p53 and its mutants in tumor cell migration and invasion. J Cell Biol. 2011;192:209–18. 21263025 10.1083/jcb.201009059 PMC3172183

81. Powell E Piwnica-Worms D Piwnica-Worms H Contribution of p53 to metastasis Cancer Discov 2014 4 405 14 10.1158/2159-8290.CD-13-0136 24658082 PMC4063123 Powell E, Piwnica-Worms D, Piwnica-Worms H. Contribution of p53 to metastasis. Cancer Discov. 2014;4:405–14. 24658082 10.1158/2159-8290.CD-13-0136 PMC4063123

82. Hanel W Marchenko N Xu S Yu SX Weng W Moll U Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis Cell Death Differ 2013 20 898 909 10.1038/cdd.2013.17 23538418 PMC3679454 Hanel W, Marchenko N, Xu S, Yu SX, Weng W, Moll U. Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. Cell Death Differ. 2013;20:898–909. 23538418 10.1038/cdd.2013.17 PMC3679454

83. Olive KP Tuveson DA Ruhe ZC Yin B Willis NA Bronson RT Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome Cell 2004 119 847 60 10.1016/j.cell.2004.11.004 15607980 Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004;119:847–60. 15607980 10.1016/j.cell.2004.11.004

84. Adorno M Cordenonsi M Montagner M Dupont S Wong C Hann B A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis Cell 2009 137 87 98 10.1016/j.cell.2009.01.039 19345189 Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, et al. A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell. 2009;137:87–98. 19345189 10.1016/j.cell.2009.01.039

85. Haupt Y Maya R Kazaz A Oren M Mdm2 promotes the rapid degradation of p53 Nature 1997 387 296 9 10.1038/387296a0 9153395 Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–9. 9153395 10.1038/387296a0

86. Kubbutat MH Jones SN Vousden KH Regulation of p53 stability by Mdm2 Nature 1997 387 299 303 10.1038/387299a0 9153396 Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997;387:299–303. 9153396 10.1038/387299a0

87. Jones SN Roe AE Donehower LA Bradley A Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53 Nature 1995 378 206 8 10.1038/378206a0 7477327 Jones SN, Roe AE, Donehower LA, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995;378:206–8. 7477327 10.1038/378206a0

88. Montes de Oca Luna R Wagner DS Lozano G Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53 Nature 1995 378 203 6 10.1038/378203a0 7477326 Montes de Oca Luna R, Wagner DS, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995;378:203–6. 7477326 10.1038/378203a0

89. Li M Brooks CL Wu-Baer F Chen D Baer R Gu W Mono- versus polyubiquitination: differential control of p53 fate by Mdm2 Science 2003 302 1972 5 10.1126/science.1091362 14671306 Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W. Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science. 2003;302:1972–5. 14671306 10.1126/science.1091362

90. Shvarts A Steegenga WT Riteco N van Laar T Dekker P Bazuine M MDMX: a novel p53-binding protein with some functional properties of MDM2 EMBO J 1996 15 5349 57 10.1002/j.1460-2075.1996.tb00919.x 8895579 PMC452278 Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M, et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 1996;15:5349–57. 8895579 PMC452278

91. Marine JC Francoz S Maetens M Wahl G Toledo F Lozano G Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4 Cell Death Differ 2006 13 927 34 10.1038/sj.cdd.4401912 16543935 Marine JC, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 2006;13:927–34. 16543935 10.1038/sj.cdd.4401912

92. Finch RA Donoviel DB Potter D Shi M Fan A Freed DD mdmx is a negative regulator of p53 activity in vivo Cancer Res 2002 62 3221 5 12036937 Finch RA, Donoviel DB, Potter D, Shi M, Fan A, Freed DD, et al. mdmx is a negative regulator of p53 activity in vivo. Cancer Res. 2002;62:3221–5. 12036937

93. Parant J Chavez-Reyes A Little NA Yan W Reinke V Jochemsen AG Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53 Nat Genet 2001 29 92 5 10.1038/ng714 11528400 Parant J, Chavez-Reyes A, Little NA, Yan W, Reinke V, Jochemsen AG, et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat Genet. 2001;29:92–5. 11528400 10.1038/ng714

94. Leng R Lin Y Ma W Wu H Lemmers B Chung S Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation Cell 2003 112 779 91 10.1016/S0092-8674(03)00193-4 12654245 Leng R, Lin Y, Ma W, Wu H, Lemmers B, Chung S, et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell. 2003;112:779–91. 12654245 10.1016/s0092-8674(03)00193-4

95. Wu H Zeinab RA Flores ER Leng R Pirh2, a ubiquitin E3 ligase, inhibits p73 transcriptional activity by promoting its ubiquitination Mol Cancer Res 2011 9 1780 90 10.1158/1541-7786.MCR-11-0157 21994467 Wu H, Zeinab RA, Flores ER, Leng R. Pirh2, a ubiquitin E3 ligase, inhibits p73 transcriptional activity by promoting its ubiquitination. Mol Cancer Res. 2011;9:1780–90. 21994467 10.1158/1541-7786.MCR-11-0157

96. Abou Zeinab R Wu HH Abuetabh Y Leng S Sergi C Eisenstat DD Pirh2, an E3 ligase, regulates the AIP4-p73 regulatory pathway by modulating AIP4 expression and ubiquitination Carcinogenesis 2021 42 650 62 10.1093/carcin/bgab009 33569599 PMC8086772 Abou Zeinab R, Wu HH, Abuetabh Y, Leng S, Sergi C, Eisenstat DD, et al. Pirh2, an E3 ligase, regulates the AIP4-p73 regulatory pathway by modulating AIP4 expression and ubiquitination. Carcinogenesis. 2021;42:650–62. 33569599 10.1093/carcin/bgab009 PMC8086772

97. Hakem A Bohgaki M Lemmers B Tai E Salmena L Matysiak-Zablocki E Role of Pirh2 in mediating the regulation of p53 and c-Myc PLoS Genet 2011 7 e1002360 10.1371/journal.pgen.1002360 22125490 PMC3219591 Hakem A, Bohgaki M, Lemmers B, Tai E, Salmena L, Matysiak-Zablocki E, et al. Role of Pirh2 in mediating the regulation of p53 and c-Myc. PLoS Genet. 2011;7:e1002360. 22125490 10.1371/journal.pgen.1002360 PMC3219591

98. Shi C Liu S Tian X Wang X Gao P A TP53 mutation model for the prediction of prognosis and therapeutic responses in head and neck squamous cell carcinoma BMC Cancer 2021 21 1035 10.1186/s12885-021-08765-w 34530752 PMC8447564 Shi C, Liu S, Tian X, Wang X, Gao P. A TP53 mutation model for the prediction of prognosis and therapeutic responses in head and neck squamous cell carcinoma. BMC Cancer. 2021;21:1035. 34530752 10.1186/s12885-021-08765-w PMC8447564

99. Maddah MM Hedayatizadeh-Omran A Moosazadeh M Alizadeh-Navaei R Evaluation of the Prognostic Role of TP53 Gene Mutations in Prostate Cancer Outcome: A Systematic Review and Meta-Analysis Clin Genitourin Cancer 2024 22 102226 10.1016/j.clgc.2024.102226 39393313 Maddah MM, Hedayatizadeh-Omran A, Moosazadeh M, Alizadeh-Navaei R. Evaluation of the Prognostic Role of TP53 Gene Mutations in Prostate Cancer Outcome: A Systematic Review and Meta-Analysis. Clin Genitourin Cancer. 2024;22:102226. 39393313 10.1016/j.clgc.2024.102226

100. Schaafsma E Takacs EM Kaur S Cheng C Kurokawa M Predicting clinical outcomes of cancer patients with a p53 deficiency gene signature Sci Rep 2022 12 1317 10.1038/s41598-022-05243-6 35079034 PMC8789768 Schaafsma E, Takacs EM, Kaur S, Cheng C, Kurokawa M. Predicting clinical outcomes of cancer patients with a p53 deficiency gene signature. Sci Rep. 2022;12:1317. 35079034 10.1038/s41598-022-05243-6 PMC8789768

101. Zhu G Pan C Bei JX Li B Liang C Xu Y Mutant p53 in Cancer Progression and Targeted Therapies Front Oncol 2020 10 595187 10.3389/fonc.2020.595187 33240819 PMC7677253 Zhu G, Pan C, Bei JX, Li B, Liang C, Xu Y, et al. Mutant p53 in Cancer Progression and Targeted Therapies. Front Oncol. 2020;10:595187. 33240819 10.3389/fonc.2020.595187 PMC7677253

102. Carlsen L Zhang S Tian X De La Cruz A George A Arnoff TE The role of p53 in anti-tumor immunity and response to immunotherapy Front Mol Biosci 2023 10 1148389 10.3389/fmolb.2023.1148389 37602328 PMC10434531 Carlsen L, Zhang S, Tian X, De La Cruz A, George A, Arnoff TE, et al. The role of p53 in anti-tumor immunity and response to immunotherapy. Front Mol Biosci. 2023;10:1148389. 37602328 10.3389/fmolb.2023.1148389 PMC10434531

103. Duffy MJ, Tang M, Rajaram S, O’Grady S, Crown J. Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use? Cancers (Basel) 2022;14. 10.3390/cancers14184499 PMC9496879 36139658

104. Wilkie MD Anaam EA Lau AS Rubbi CP Jones TM Boyd MT TP53 mutations in head and neck cancer cells determine the Warburg phenotypic switch creating metabolic vulnerabilities and therapeutic opportunities for stratified therapies Cancer Lett 2020 478 107 21 10.1016/j.canlet.2020.02.032 32113989 PMC7133053 Wilkie MD, Anaam EA, Lau AS, Rubbi CP, Jones TM, Boyd MT, et al. TP53 mutations in head and neck cancer cells determine the Warburg phenotypic switch creating metabolic vulnerabilities and therapeutic opportunities for stratified therapies. Cancer Lett. 2020;478:107–21. 32113989 10.1016/j.canlet.2020.02.032 PMC7133053

105. Lu Y, Wu M, Xu Y, Yu L. The Development of p53-Targeted Therapies for Human Cancers. Cancers (Basel) 2023;15. 10.3390/cancers15143560 PMC10377496 37509223

106. Cancer Genome Atlas N Comprehensive molecular portraits of human breast tumours Nature 2012 490 61 70 10.1038/nature11412 23000897 PMC3465532 Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70. 23000897 10.1038/nature11412 PMC3465532

107. de Andrade KC Lee EE Tookmanian EM Kesserwan CA Manfredi JJ Hatton JN The TP53 Database: transition from the International Agency for Research on Cancer to the US National Cancer Institute Cell Death Differ 2022 29 1071 3 10.1038/s41418-022-00976-3 35352025 PMC9090805 de Andrade KC, Lee EE, Tookmanian EM, Kesserwan CA, Manfredi JJ, Hatton JN, et al. The TP53 Database: transition from the International Agency for Research on Cancer to the US National Cancer Institute. Cell Death Differ. 2022;29:1071–3. 35352025 10.1038/s41418-022-00976-3 PMC9090805

108. Chen T Ashwood LM Kondrashova O Strasser A Kelly G Sutherland KD Breathing new insights into the role of mutant p53 in lung cancer Oncogene 2025 44 115 29 10.1038/s41388-024-03219-6 39567755 PMC11725503 Chen T, Ashwood LM, Kondrashova O, Strasser A, Kelly G, Sutherland KD. Breathing new insights into the role of mutant p53 in lung cancer. Oncogene. 2025;44:115–29. 39567755 10.1038/s41388-024-03219-6 PMC11725503

109. Tracewell MA, Karlin JE, Barnada SM, McDuffie EL, Scott CP, Barta JA et al. Somatic p53 mutations that are markedly overrepresented in lung cancer confer resistance to reactive oxygen species-induced cell death. Carcinogenesis 2025;46. 10.1093/carcin/bgaf027 40458924

110. Jeong M, Kim KB. Recent Research on Role of p53 Family in Small-Cell Lung Cancer. Cancers (Basel) 2025;17. 10.3390/cancers17071110 PMC11988120 40227619

111. Warren RS Atreya CE Niedzwiecki D Weinberg VK Donner DB Mayer RJ Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803 Clin Cancer Res 2013 19 5777 87 10.1158/1078-0432.CCR-13-0351 23983256 PMC4122229 Warren RS, Atreya CE, Niedzwiecki D, Weinberg VK, Donner DB, Mayer RJ, et al. Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803. Clin Cancer Res. 2013;19:5777–87. 23983256 10.1158/1078-0432.CCR-13-0351 PMC4122229

112. Liebl MC, Hofmann TG. The Role of p53 Signaling in Colorectal Cancer. Cancers (Basel) 2021;13. 10.3390/cancers13092125 PMC8125348 33924934

113. Nakayama M Oshima M Mutant p53 in colon cancer J Mol Cell Biol 2019 11 267 76 10.1093/jmcb/mjy075 30496442 PMC6487790 Nakayama M, Oshima M. Mutant p53 in colon cancer. J Mol Cell Biol. 2019;11:267–76. 30496442 10.1093/jmcb/mjy075 PMC6487790

114. Zhang Y, Dube C, Gibert M Jr., Cruickshanks N, Wang B, Coughlan M et al. The p53 Pathway in Glioblastoma. Cancers (Basel) 2018;10. 10.3390/cancers10090297 PMC6162501 30200436

115. Roshandel AK Busch CM Mullekom JV Cuoco JA Rogers CM Apfel LS The predictive capability of immunohistochemistry and DNA sequencing for determining TP53 functional mutation status: a comparative study of 41 glioblastoma patients Oncotarget 2019 10 6204 18 10.18632/oncotarget.27252 31692772 PMC6817445 Roshandel AK, Busch CM, Mullekom JV, Cuoco JA, Rogers CM, Apfel LS, et al. The predictive capability of immunohistochemistry and DNA sequencing for determining TP53 functional mutation status: a comparative study of 41 glioblastoma patients. Oncotarget. 2019;10:6204–18. 31692772 10.18632/oncotarget.27252 PMC6817445

116. Ham SW Jeon HY Jin X Kim EJ Kim JK Shin YJ TP53 gain-of-function mutation promotes inflammation in glioblastoma Cell Death Differ 2019 26 409 25 10.1038/s41418-018-0126-3 29786075 PMC6370770 Ham SW, Jeon HY, Jin X, Kim EJ, Kim JK, Shin YJ, et al. TP53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death Differ. 2019;26:409–25. 29786075 10.1038/s41418-018-0126-3 PMC6370770

117. Wallis B, Bowman KR, Lu P, Lim CS. The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer. Biomolecules 2023;13. 10.3390/biom13010159 PMC9855757 36671544

118. Cole AJ Dwight T Gill AJ Dickson KA Zhu Y Clarkson A Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing Sci Rep 2016 6 26191 10.1038/srep26191 27189670 PMC4870633 Cole AJ, Dwight T, Gill AJ, Dickson KA, Zhu Y, Clarkson A, et al. Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing. Sci Rep. 2016;6:26191. 27189670 10.1038/srep26191 PMC4870633

119. Tuna M Ju Z Yoshihara K Amos CI Tanyi JL Mills GB Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers Br J Cancer 2020 122 405 12 10.1038/s41416-019-0654-8 31780779 PMC7000721 Tuna M, Ju Z, Yoshihara K, Amos CI, Tanyi JL, Mills GB. Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers. Br J Cancer. 2020;122:405–12. 31780779 10.1038/s41416-019-0654-8 PMC7000721

120. Guha T, Malkin D. Inherited TP53 Mutations and the Li-Fraumeni Syndrome. Cold Spring Harb Perspect Med 2017;7. 10.1101/cshperspect.a026187 PMC5378014 28270529

121. Frebourg T Bajalica Lagercrantz S Oliveira C Magenheim R Evans DG European Reference Network G. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes Eur J Hum Genet 2020 28 1379 86 10.1038/s41431-020-0638-4 32457520 PMC7609280 Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG. European Reference Network G. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. 2020;28:1379–86. 32457520 10.1038/s41431-020-0638-4 PMC7609280

122. Hamada M Fujiwara T Hizuta A Gochi A Naomoto Y Takakura N The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers J Cancer Res Clin Oncol 1996 122 360 5 10.1007/BF01220804 8642047 PMC12200597 Hamada M, Fujiwara T, Hizuta A, Gochi A, Naomoto Y, Takakura N, et al. The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers. J Cancer Res Clin Oncol. 1996;122:360–5. 8642047 10.1007/BF01220804 PMC12200597

123. Zhang S, Carlsen L, Hernandez Borrero L, Seyhan AA, Tian X, El-Deiry WS. Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules 2022;12. 10.3390/biom12040548 PMC9029346 35454137

124. Babamohamadi M Babaei E Ahmed Salih B Babamohammadi M Jalal Azeez H Othman G Recent findings on the role of wild-type and mutant p53 in cancer development and therapy Front Mol Biosci 2022 9 903075 10.3389/fmolb.2022.903075 36225257 PMC9549909 Babamohamadi M, Babaei E, Ahmed Salih B, Babamohammadi M, Jalal Azeez H, Othman G. Recent findings on the role of wild-type and mutant p53 in cancer development and therapy. Front Mol Biosci. 2022;9:903075. 36225257 10.3389/fmolb.2022.903075 PMC9549909

125. Dong ZY Zhong WZ Zhang XC Su J Xie Z Liu SY Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma Clin Cancer Res 2017 23 3012 24 10.1158/1078-0432.CCR-16-2554 28039262 Dong ZY, Zhong WZ, Zhang XC, Su J, Xie Z, Liu SY, et al. Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2017;23:3012–24. 28039262 10.1158/1078-0432.CCR-16-2554

126. Skoulidis F Goldberg ME Greenawalt DM Hellmann MD Awad MM Gainor JF STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma Cancer Discov 2018 8 822 35 10.1158/2159-8290.CD-18-0099 29773717 PMC6030433 Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov. 2018;8:822–35. 29773717 10.1158/2159-8290.CD-18-0099 PMC6030433

127. Wu HH Leng S Eisenstat DD Sergi C Leng R Targeting p53 for immune modulation: Exploring its functions in tumor immunity and inflammation Cancer Lett 2025 617 217614 10.1016/j.canlet.2025.217614 40054656 Wu HH, Leng S, Eisenstat DD, Sergi C, Leng R. Targeting p53 for immune modulation: Exploring its functions in tumor immunity and inflammation. Cancer Lett. 2025;617:217614. 40054656 10.1016/j.canlet.2025.217614

128. Blagih J, Buck MD, Vousden KH. p53, cancer and the immune response. J Cell Sci 2020;133. 10.1242/jcs.237453 32144194

129. Cooks T Pateras IS Jenkins LM Patel KM Robles AI Morris J Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246 Nat Commun 2018 9 771 10.1038/s41467-018-03224-w 29472616 PMC5823939 Cooks T, Pateras IS, Jenkins LM, Patel KM, Robles AI, Morris J, et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun. 2018;9:771. 29472616 10.1038/s41467-018-03224-w PMC5823939

130. Riaz N Morris L Havel JJ Makarov V Desrichard A Chan TA The role of neoantigens in response to immune checkpoint blockade Int Immunol 2016 28 411 9 10.1093/intimm/dxw019 27048318 PMC4986233 Riaz N, Morris L, Havel JJ, Makarov V, Desrichard A, Chan TA. The role of neoantigens in response to immune checkpoint blockade. Int Immunol. 2016;28:411–9. 27048318 10.1093/intimm/dxw019 PMC4986233

131. Kandoth C McLellan MD Vandin F Ye K Niu B Lu C Mutational landscape and significance across 12 major cancer types Nature 2013 502 333 9 10.1038/nature12634 24132290 PMC3927368 Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9. 24132290 10.1038/nature12634 PMC3927368

132. Robles AI Harris CC Clinical outcomes and correlates of TP53 mutations and cancer Cold Spring Harb Perspect Biol 2010 2 a001016 10.1101/cshperspect.a001016 20300207 PMC2829964 Robles AI, Harris CC. Clinical outcomes and correlates of TP53 mutations and cancer. Cold Spring Harb Perspect Biol. 2010;2:a001016. 20300207 10.1101/cshperspect.a001016 PMC2829964

133. Midgley RS Kerr DJ Immunotherapy for colorectal cancer Expert Rev Anticancer Ther 2003 3 63 78 10.1586/14737140.3.1.63 12597351 Midgley RS, Kerr DJ. Immunotherapy for colorectal cancer. Expert Rev Anticancer Ther. 2003;3:63–78. 12597351 10.1586/14737140.3.1.63

134. Kogan S Carpizo D Pharmacological targeting of mutant p53 Transl Cancer Res 2016 5 698 706 10.21037/tcr.2016.11.74 30956950 PMC6448797 Kogan S, Carpizo D. Pharmacological targeting of mutant p53. Transl Cancer Res. 2016;5:698–706. 30956950 10.21037/tcr.2016.11.74 PMC6448797

135. Bykov VJ Selivanova G Wiman KG Small molecules that reactivate mutant p53 Eur J Cancer 2003 39 1828 34 10.1016/S0959-8049(03)00454-4 12932659 Bykov VJ, Selivanova G, Wiman KG. Small molecules that reactivate mutant p53. Eur J Cancer. 2003;39:1828–34. 12932659 10.1016/s0959-8049(03)00454-4

136. Guiley KZ Shokat KM A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability Cancer Discov 2023 13 56 69 10.1158/2159-8290.CD-22-0381 36197521 PMC9827106 Guiley KZ, Shokat KM. A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability. Cancer Discov. 2023;13:56–69. 36197521 10.1158/2159-8290.CD-22-0381 PMC9827106

137. Liu X Wilcken R Joerger AC Chuckowree IS Amin J Spencer J Small molecule induced reactivation of mutant p53 in cancer cells Nucleic Acids Res 2013 41 6034 44 10.1093/nar/gkt305 23630318 PMC3695503 Liu X, Wilcken R, Joerger AC, Chuckowree IS, Amin J, Spencer J, et al. Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res. 2013;41:6034–44. 23630318 10.1093/nar/gkt305 PMC3695503

138. Peng Z Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers Hum Gene Ther 2005 16 1016 27 10.1089/hum.2005.16.1016 16149900 Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther. 2005;16:1016–27. 16149900 10.1089/hum.2005.16.1016

139. Zhang WW Li L Li D Liu J Li X Li W The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic Hum Gene Ther 2018 29 160 79 10.1089/hum.2017.218 29338444 Zhang WW, Li L, Li D, Liu J, Li X, Li W, et al. The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic. Hum Gene Ther. 2018;29:160–79. 29338444 10.1089/hum.2017.218

140. Gabrilovich DI INGN 201 (Advexin): adenoviral p53 gene therapy for cancer Expert Opin Biol Ther 2006 6 823 32 10.1517/14712598.6.8.823 16856803 Gabrilovich DI. INGN 201 (Advexin): adenoviral p53 gene therapy for cancer. Expert Opin Biol Ther. 2006;6:823–32. 16856803 10.1517/14712598.6.8.823

141. Ries S Korn WM ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus Br J Cancer 2002 86 5 11 10.1038/sj.bjc.6600006 11857003 PMC2746528 Ries S, Korn WM. ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus. Br J Cancer. 2002;86:5–11. 11857003 10.1038/sj.bjc.6600006 PMC2746528

142. Nemunaitis J Khuri F Ganly I Arseneau J Posner M Vokes E Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer J Clin Oncol 2001 19 289 98 10.1200/JCO.2001.19.2.289 11208818 Nemunaitis J, Khuri F, Ganly I, Arseneau J, Posner M, Vokes E, et al. Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol. 2001;19:289–98. 11208818 10.1200/JCO.2001.19.2.289

143. Mitchell MJ Billingsley MM Haley RM Wechsler ME Peppas NA Langer R Engineering precision nanoparticles for drug delivery Nat Rev Drug Discov 2021 20 101 24 10.1038/s41573-020-0090-8 33277608 PMC7717100 Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20:101–24. 33277608 10.1038/s41573-020-0090-8 PMC7717100

144. Cong L Zhang F Genome engineering using CRISPR-Cas9 system Methods Mol Biol 2015 1239 197 217 10.1007/978-1-4939-1862-1_10 25408407 Cong L, Zhang F. Genome engineering using CRISPR-Cas9 system. Methods Mol Biol. 2015;1239:197–217. 25408407 10.1007/978-1-4939-1862-1_10

145. Ran FA Hsu PD Wright J Agarwala V Scott DA Zhang F Genome engineering using the CRISPR-Cas9 system Nat Protoc 2013 8 2281 308 10.1038/nprot.2013.143 24157548 PMC3969860 Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281–308. 24157548 10.1038/nprot.2013.143 PMC3969860

146. Mascarenhas JO Bose P Hou HA Homenda W Ross D Mohan SR Disease-Modifying Activity of Navtemadlin Correlates with Clinical Responses in a Randomized, Multicenter, Global Phase 3 Study (BOREAS) in JAK-Inhibitor Relapsed/Refractory Myelofibrosis Blood 2024 144 483 5 10.1182/blood-2024-205937 Mascarenhas JO, Bose P, Hou HA, Homenda W, Ross D, Mohan SR, et al. Disease-Modifying Activity of Navtemadlin Correlates with Clinical Responses in a Randomized, Multicenter, Global Phase 3 Study (BOREAS) in JAK-Inhibitor Relapsed/Refractory Myelofibrosis. Blood. 2024;144:483–5.

147. Mascarenhas JO Popov VM Mohan S Özkurt ZN Kiladjian JJ Al-Ali HK Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis Blood 2024 144 1000 1 10.1182/blood-2024-201642 Mascarenhas JO, Popov VM, Mohan S, Özkurt ZN, Kiladjian JJ, Al-Ali HK, et al. Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis. Blood. 2024;144:1000–1.

148. Tovar C Rosinski J Filipovic Z Higgins B Kolinsky K Hilton H Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy Proc Natl Acad Sci U S A 2006 103 1888 93 10.1073/pnas.0507493103 16443686 PMC1413632 Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A. 2006;103:1888–93. 16443686 10.1073/pnas.0507493103 PMC1413632

149. Vassilev LT Vu BT Graves B Carvajal D Podlaski F Filipovic Z In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 Science 2004 303 844 8 10.1126/science.1092472 14704432 Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8. 14704432 10.1126/science.1092472

150. Vu B Wovkulich P Pizzolato G Lovey A Ding Q Jiang N Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development ACS Med Chem Lett 2013 4 466 9 10.1021/ml4000657 24900694 PMC4027145 Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, et al. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. ACS Med Chem Lett. 2013;4:466–9. 24900694 10.1021/ml4000657 PMC4027145

151. Huang Y, Li W, Zhou Y, Bai J, Li N, Su Z et al. Strategies for p53 Activation and Targeted Inhibitors of the p53-Mdm2/MdmX Interaction. Cells 2025; 14. 10.3390/cells14080583 PMC12025665 40277907

152. Shen H Maki CG Pharmacologic activation of p53 by small-molecule MDM2 antagonists Curr Pharm Des 2011 17 560 8 10.2174/138161211795222603 21391906 PMC3613239 Shen H, Maki CG. Pharmacologic activation of p53 by small-molecule MDM2 antagonists. Curr Pharm Des. 2011;17:560–8. 21391906 10.2174/138161211795222603 PMC3613239

153. Khurana A Shafer DA MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388) Onco Targets Ther 2019 12 2903 10 10.2147/OTT.S172315 31289443 PMC6563714 Khurana A, Shafer DA. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther. 2019;12:2903–10. 31289443 10.2147/OTT.S172315 PMC6563714

154. Sallman DA DeZern AE Garcia-Manero G Steensma DP Roboz GJ Sekeres MA Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes J Clin Oncol 2021 39 1584 94 10.1200/JCO.20.02341 33449813 PMC8099410 Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, et al. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol. 2021;39:1584–94. 33449813 10.1200/JCO.20.02341 PMC8099410

155. Puzio-Kuter AM Xu L McBrayer MK Dominique R Li HH Fahr BJ Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small-Molecule Reactivator Cancer Discov 2025 15 1159 79 10.1158/2159-8290.CD-24-1421 39945593 PMC12130801 Puzio-Kuter AM, Xu L, McBrayer MK, Dominique R, Li HH, Fahr BJ, et al. Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small-Molecule Reactivator. Cancer Discov. 2025;15:1159–79. 39945593 10.1158/2159-8290.CD-24-1421 PMC12130801

156. Lindemann A Patel AA Silver NL Tang L Liu Z Wang L COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms Clin Cancer Res 2019 25 5650 62 10.1158/1078-0432.CCR-19-0096 31308060 PMC6759991 Lindemann A, Patel AA, Silver NL, Tang L, Liu Z, Wang L, et al. COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms. Clin Cancer Res. 2019;25:5650–62. 31308060 10.1158/1078-0432.CCR-19-0096 PMC6759991

157. Yu X Kogan S Chen Y Tsang AT Withers T Lin H Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics Clin Cancer Res 2018 24 4505 17 10.1158/1078-0432.CCR-18-0822 29914895 PMC6139040 Yu X, Kogan S, Chen Y, Tsang AT, Withers T, Lin H, et al. Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics. Clin Cancer Res. 2018;24:4505–17. 29914895 10.1158/1078-0432.CCR-18-0822 PMC6139040

158. Peng Y Chen L Li C Lu W Chen J Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization J Biol Chem 2001 276 40583 90 10.1074/jbc.M102817200 11507088 Peng Y, Chen L, Li C, Lu W, Chen J. Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. J Biol Chem. 2001;276:40583–90. 11507088 10.1074/jbc.M102817200

159. Li D Marchenko ND Schulz R Fischer V Velasco-Hernandez T Talos F Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells Mol Cancer Res 2011 9 577 88 10.1158/1541-7786.MCR-10-0534 21478269 PMC3097033 Li D, Marchenko ND, Schulz R, Fischer V, Velasco-Hernandez T, Talos F, et al. Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells. Mol Cancer Res. 2011;9:577–88. 21478269 10.1158/1541-7786.MCR-10-0534 PMC3097033

160. Youssef ME, Cavalu S, Hasan AM, Yahya G, Abd-Eldayem MA, Saber S. Role of Ganetespib, an HSP90 Inhibitor, in Cancer Therapy: From Molecular Mechanisms to Clinical Practice. Int J Mol Sci 2023;24. 10.3390/ijms24055014 PMC10002602 36902446

161. Isermann T Schneider KL Wegwitz F De Oliveira T Conradi LC Volk V Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition Cell Death Differ 2025 32 1734 49 10.1038/s41418-025-01502-x 40204953 PMC12432187 Isermann T, Schneider KL, Wegwitz F, De Oliveira T, Conradi LC, Volk V, et al. Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition. Cell Death Differ. 2025;32:1734–49. 40204953 10.1038/s41418-025-01502-x PMC12432187

162. Brochier C Dennis G Rivieccio MA McLaughlin K Coppola G Ratan RR Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons J Neurosci 2013 33 8621 32 10.1523/JNEUROSCI.5214-12.2013 23678107 PMC6618832 Brochier C, Dennis G, Rivieccio MA, McLaughlin K, Coppola G, Ratan RR, et al. Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. J Neurosci. 2013;33:8621–32. 23678107 10.1523/JNEUROSCI.5214-12.2013 PMC6618832

163. Roy S Packman K Jeffrey R Tenniswood M Histone deacetylase inhibitors differentially stabilize acetylated p53 and induce cell cycle arrest or apoptosis in prostate cancer cells Cell Death Differ 2005 12 482 91 10.1038/sj.cdd.4401581 15746940 Roy S, Packman K, Jeffrey R, Tenniswood M. Histone deacetylase inhibitors differentially stabilize acetylated p53 and induce cell cycle arrest or apoptosis in prostate cancer cells. Cell Death Differ. 2005;12:482–91. 15746940 10.1038/sj.cdd.4401581

164. El Omari N Bakrim S Elhrech H Aanniz T Balahbib A Lee LH Clinical efficacy and mechanistic insights of FDA-approved HDAC inhibitors in the treatment of lymphoma Eur J Pharm Sci 2025 208 107057 10.1016/j.ejps.2025.107057 40043823 El Omari N, Bakrim S, Elhrech H, Aanniz T, Balahbib A, Lee LH, et al. Clinical efficacy and mechanistic insights of FDA-approved HDAC inhibitors in the treatment of lymphoma. Eur J Pharm Sci. 2025;208:107057. 40043823 10.1016/j.ejps.2025.107057

165. Lu G Jin S Lin S Gong Y Zhang L Yang J Update on histone deacetylase inhibitors in peripheral T-cell lymphoma (PTCL) Clin Epigenetics 2023 15 124 10.1186/s13148-023-01531-8 37533111 PMC10398948 Lu G, Jin S, Lin S, Gong Y, Zhang L, Yang J, et al. Update on histone deacetylase inhibitors in peripheral T-cell lymphoma (PTCL). Clin Epigenetics. 2023;15:124. 37533111 10.1186/s13148-023-01531-8 PMC10398948

166. Prince HM Dickinson M Romidepsin for cutaneous T-cell lymphoma Clin Cancer Res 2012 18 3509 15 10.1158/1078-0432.CCR-11-3144 22535155 Prince HM, Dickinson M. Romidepsin for cutaneous T-cell lymphoma. Clin Cancer Res. 2012;18:3509–15. 22535155 10.1158/1078-0432.CCR-11-3144

167. Li X Pu W Zheng Q Ai M Chen S Peng Y Proteolysis-targeting chimeras (PROTACs) in cancer therapy Mol Cancer 2022 21 99 10.1186/s12943-021-01434-3 35410300 PMC8996410 Li X, Pu W, Zheng Q, Ai M, Chen S, Peng Y. Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Mol Cancer. 2022;21:99. 35410300 10.1186/s12943-021-01434-3 PMC8996410

168. Rahman MA Park MN Rahman MH Rashid MM Islam R Uddin MJ p53 Modulation of Autophagy Signaling in Cancer Therapies: Perspectives Mechanism and Therapeutic Targets Front Cell Dev Biol 2022 10 761080 10.3389/fcell.2022.761080 35155422 PMC8827382 Rahman MA, Park MN, Rahman MH, Rashid MM, Islam R, Uddin MJ, et al. p53 Modulation of Autophagy Signaling in Cancer Therapies: Perspectives Mechanism and Therapeutic Targets. Front Cell Dev Biol. 2022;10:761080. 35155422 10.3389/fcell.2022.761080 PMC8827382

169. Shi Y Norberg E Vakifahmetoglu-Norberg H Mutant p53 as a Regulator and Target of Autophagy Front Oncol 2020 10 607149 10.3389/fonc.2020.607149 33614491 PMC7886977 Shi Y, Norberg E, Vakifahmetoglu-Norberg H. Mutant p53 as a Regulator and Target of Autophagy. Front Oncol. 2020;10:607149. 33614491 10.3389/fonc.2020.607149 PMC7886977

170. Sui X Chen R Wang Z Huang Z Kong N Zhang M Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment Cell Death Dis 2013 4 e838 10.1038/cddis.2013.350 24113172 PMC3824660 Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838. 24113172 10.1038/cddis.2013.350 PMC3824660

171. Manic G Obrist F Kroemer G Vitale I Galluzzi L Chloroquine and hydroxychloroquine for cancer therapy Mol Cell Oncol 2014 1 e29911 10.4161/mco.29911 27308318 PMC4905171 Manic G, Obrist F, Kroemer G, Vitale I, Galluzzi L. Chloroquine and hydroxychloroquine for cancer therapy. Mol Cell Oncol. 2014;1:e29911. 27308318 10.4161/mco.29911 PMC4905171

172. Du C Wu H Leng R UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation Oncotarget 2016 7 2823 36 10.18632/oncotarget.6555 26673821 PMC4823074 Du C, Wu H, Leng R. UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation. Oncotarget. 2016;7:2823–36. 26673821 10.18632/oncotarget.6555 PMC4823074

173. Abuetabh Y Wu HH Al Yousef H Persad S Schlosser MP Eisenstat DD Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage Cell Death Discov 2025 11 131 10.1038/s41420-025-02441-9 40175346 PMC11965332 Abuetabh Y, Wu HH, Al Yousef H, Persad S, Schlosser MP, Eisenstat DD, et al. Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage. Cell Death Discov. 2025;11:131. 40175346 10.1038/s41420-025-02441-9 PMC11965332

174. Enge M Bao W Hedstrom E Jackson SP Moumen A Selivanova G MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53 Cancer Cell 2009 15 171 83 10.1016/j.ccr.2009.01.019 19249676 Enge M, Bao W, Hedstrom E, Jackson SP, Moumen A, Selivanova G. MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53. Cancer Cell. 2009;15:171–83. 19249676 10.1016/j.ccr.2009.01.019

175. Cash T Fox E Liu X Minard CG Reid JM Scheck AC A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children’s Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515) Pediatr Blood Cancer 2021 68 e29065 10.1002/pbc.29065 33881209 PMC9090141 Cash T, Fox E, Liu X, Minard CG, Reid JM, Scheck AC, et al. A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children’s Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515). Pediatr Blood Cancer. 2021;68:e29065. 33881209 10.1002/pbc.29065 PMC9090141

176. Di Ghelli Luserna A Iacobucci I Imbrogno E Papayannidis C Derenzini E Ferrari A Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia Oncotarget 2016 7 53377 91 10.18632/oncotarget.10535 27438145 PMC5288194 Di Ghelli Luserna A, Iacobucci I, Imbrogno E, Papayannidis C, Derenzini E, Ferrari A, et al. Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia. Oncotarget. 2016;7:53377–91. 27438145 10.18632/oncotarget.10535 PMC5288194

177. van Harten AM Buijze M van der Mast R Rooimans MA Martens-de Kemp SR Bachas C Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death Oncogenesis 2019 8 38 10.1038/s41389-019-0147-x 31209198 PMC6572811 van Harten AM, Buijze M, van der Mast R, Rooimans MA, Martens-de Kemp SR, Bachas C, et al. Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. Oncogenesis. 2019;8:38. 31209198 10.1038/s41389-019-0147-x PMC6572811

178. Melia E Fisch AS Tinhofer I Parsons JL Targeting Chk1 and Wee1 kinases enhances radiosensitivity of 2D and 3D head and neck cancer models to X-rays and low/high-LET protons Cell Death Dis 2025 16 128 10.1038/s41419-025-07435-0 39994186 PMC11850709 Melia E, Fisch AS, Tinhofer I, Parsons JL. Targeting Chk1 and Wee1 kinases enhances radiosensitivity of 2D and 3D head and neck cancer models to X-rays and low/high-LET protons. Cell Death Dis. 2025;16:128. 39994186 10.1038/s41419-025-07435-0 PMC11850709

179. Guler S DiPoto MC Crespo A Caldwell R Doerfel B Grossmann N Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression ACS Med Chem Lett 2023 14 566 76 10.1021/acsmedchemlett.2c00481 37197456 PMC10184160 Guler S, DiPoto MC, Crespo A, Caldwell R, Doerfel B, Grossmann N, et al. Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression. ACS Med Chem Lett. 2023;14:566–76. 37197456 10.1021/acsmedchemlett.2c00481 PMC10184160

180. Jiao X Liu J Wu Y Zhong Q Zhu L Wang L Sequential treatment with PARPi and WEE1i enhances antitumor immune responses in preclinical models of ovarian cancer Sci Transl Med 2025 17 eadu6989 10.1126/scitranslmed.adu6989 40802736 Jiao X, Liu J, Wu Y, Zhong Q, Zhu L, Wang L, et al. Sequential treatment with PARPi and WEE1i enhances antitumor immune responses in preclinical models of ovarian cancer. Sci Transl Med. 2025;17:eadu6989. 40802736 10.1126/scitranslmed.adu6989

181. Williams AB, Schumacher B. p53 in the DNA-Damage-Repair Process. Cold Spring Harb Perspect Med 2016;6. 10.1101/cshperspect.a026070 PMC4852800 27048304

182. Emami S Interplay between p53-family, their regulators, and PARPs in DNA repair Clin Res Hepatol Gastroenterol 2011 35 98 104 10.1016/j.gcb.2010.10.002 21177056 Emami S. Interplay between p53-family, their regulators, and PARPs in DNA repair. Clin Res Hepatol Gastroenterol. 2011;35:98–104. 21177056 10.1016/j.gcb.2010.10.002

183. Alruwaili MM Zonneville J Naranjo MN Serio H Melendy T Straubinger RM A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers Cell Rep Med 2024 5 101434 10.1016/j.xcrm.2024.101434 38387463 PMC10982975 Alruwaili MM, Zonneville J, Naranjo MN, Serio H, Melendy T, Straubinger RM, et al. A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers. Cell Rep Med. 2024;5:101434. 38387463 10.1016/j.xcrm.2024.101434 PMC10982975

184. Min A Im SA Jang H Kim S Lee M Kim DK AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells Mol Cancer Ther 2017 16 566 77 10.1158/1535-7163.MCT-16-0378 28138034 Min A, Im SA, Jang H, Kim S, Lee M, Kim DK, et al. AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells. Mol Cancer Ther. 2017;16:566–77. 28138034 10.1158/1535-7163.MCT-16-0378

185. Peng S Long M Chen Q Yin Z Zeng C Zhang W Perspectives on cancer therapy-synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges Cell Death Discov 2025 11 179 10.1038/s41420-025-02418-8 40240755 PMC12003663 Peng S, Long M, Chen Q, Yin Z, Zeng C, Zhang W, et al. Perspectives on cancer therapy-synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges. Cell Death Discov. 2025;11:179. 40240755 10.1038/s41420-025-02418-8 PMC12003663

186. Kwok M Davies N Agathanggelou A Smith E Petermann E Yates E Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway Lancet 2015 385 Suppl 1 S58 10.1016/S0140-6736(15)60373-7 26312880 Kwok M, Davies N, Agathanggelou A, Smith E, Petermann E, Yates E, et al. Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway. Lancet. 2015;385(Suppl 1):S58. 26312880 10.1016/S0140-6736(15)60373-7

187. Tran TQ Lowman XH Reid MA Mendez-Dorantes C Pan M Yang Y Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction Oncogene 2017 36 1991 2001 10.1038/onc.2016.360 27721412 PMC5383530 Tran TQ, Lowman XH, Reid MA, Mendez-Dorantes C, Pan M, Yang Y, et al. Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction. Oncogene. 2017;36:1991–2001. 27721412 10.1038/onc.2016.360 PMC5383530

188. Jin J Byun JK Choi YK Park KG Targeting glutamine metabolism as a therapeutic strategy for cancer Exp Mol Med 2023 55 706 15 10.1038/s12276-023-00971-9 37009798 PMC10167356 Jin J, Byun JK, Choi YK, Park KG. Targeting glutamine metabolism as a therapeutic strategy for cancer. Exp Mol Med. 2023;55:706–15. 37009798 10.1038/s12276-023-00971-9 PMC10167356

189. Tombari C Zannini A Bertolio R Pedretti S Audano M Triboli L Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth Nat Commun 2023 14 6777 10.1038/s41467-023-42458-1 37880212 PMC10600207 Tombari C, Zannini A, Bertolio R, Pedretti S, Audano M, Triboli L, et al. Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth. Nat Commun. 2023;14:6777. 37880212 10.1038/s41467-023-42458-1 PMC10600207

190. Manasanch EE Orlowski RZ Proteasome inhibitors in cancer therapy Nat Rev Clin Oncol 2017 14 417 33 10.1038/nrclinonc.2016.206 28117417 PMC5828026 Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14:417–33. 28117417 10.1038/nrclinonc.2016.206 PMC5828026

191. Ochoa TA Rossi A Woodle ES Hildeman D Allman D The Proteasome Inhibitor Bortezomib Induces p53-Dependent Apoptosis in Activated B Cells J Immunol 2024 212 154 64 10.4049/jimmunol.2300212 37966267 PMC10872551 Ochoa TA, Rossi A, Woodle ES, Hildeman D, Allman D. The Proteasome Inhibitor Bortezomib Induces p53-Dependent Apoptosis in Activated B Cells. J Immunol. 2024;212:154–64. 37966267 10.4049/jimmunol.2300212 PMC10872551

192. Xue Y Barker N Hoon S He P Thakur T Abdeen SR Bortezomib Stabilizes and Activates p53 in Proliferative Compartments of Both Normal and Tumor Tissues In Vivo Cancer Res 2019 79 3595 607 10.1158/0008-5472.CAN-18-3744 31138526 Xue Y, Barker N, Hoon S, He P, Thakur T, Abdeen SR, et al. Bortezomib Stabilizes and Activates p53 in Proliferative Compartments of Both Normal and Tumor Tissues In Vivo. Cancer Res. 2019;79:3595–607. 31138526 10.1158/0008-5472.CAN-18-3744

193. Wang B Wu H Chai C Lewis J Pichiorri F Eisenstat DD MicroRNA-1301 suppresses tumor cell migration and invasion by targeting the p53/UBE4B pathway in multiple human cancer cells Cancer Lett 2017 401 20 32 10.1016/j.canlet.2017.04.038 28483517 Wang B, Wu H, Chai C, Lewis J, Pichiorri F, Eisenstat DD, et al. MicroRNA-1301 suppresses tumor cell migration and invasion by targeting the p53/UBE4B pathway in multiple human cancer cells. Cancer Lett. 2017;401:20–32. 28483517 10.1016/j.canlet.2017.04.038

194. Vousden KH Lane DP p53 in health and disease Nat Rev Mol Cell Biol 2007 8 275 83 10.1038/nrm2147 17380161 Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8:275–83. 17380161 10.1038/nrm2147

195. Kastenhuber ER Lowe SW Putting p53 in Context Cell 2017 170 1062 78 10.1016/j.cell.2017.08.028 28886379 PMC5743327 Kastenhuber ER, Lowe SW. Putting p53 in Context. Cell. 2017;170:1062–78. 28886379 10.1016/j.cell.2017.08.028 PMC5743327

196. Donehower LA Soussi T Korkut A Liu Y Schultz A Cardenas M Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas Cell Rep 2019 28 3010 10.1016/j.celrep.2019.08.061 31509758 Donehower LA, Soussi T, Korkut A, Liu Y, Schultz A, Cardenas M, et al. Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas. Cell Rep. 2019;28:3010. 31509758 10.1016/j.celrep.2019.08.061

197. Joerger AC Fersht AR The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches Annu Rev Biochem 2016 85 375 404 10.1146/annurev-biochem-060815-014710 27145840 Joerger AC, Fersht AR. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Annu Rev Biochem. 2016;85:375–404. 27145840 10.1146/annurev-biochem-060815-014710

198. Chipuk JE Kuwana T Bouchier-Hayes L Droin NM Newmeyer DD Schuler M Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis Science 2004 303 1010 4 10.1126/science.1092734 14963330 Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004;303:1010–4. 14963330 10.1126/science.1092734

199. El-Deiry WS The role of p53 in chemosensitivity and radiosensitivity Oncogene 2003 22 7486 95 10.1038/sj.onc.1206949 14576853 El-Deiry WS. The role of p53 in chemosensitivity and radiosensitivity. Oncogene. 2003;22:7486–95. 14576853 10.1038/sj.onc.1206949

200. Vousden KH p53: death star Cell 2000 103 691 4 10.1016/S0092-8674(00)00171-9 11114324 Vousden KH. p53: death star. Cell. 2000;103:691–4. 11114324 10.1016/s0092-8674(00)00171-9

201. Cory S Adams JM The Bcl2 family: regulators of the cellular life-or-death switch Nat Rev Cancer 2002 2 647 56 10.1038/nrc883 12209154 Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2:647–56. 12209154 10.1038/nrc883

202. Lessene G Czabotar PE Colman PM BCL-2 family antagonists for cancer therapy Nat Rev Drug Discov 2008 7 989 1000 10.1038/nrd2658 19043450 Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008;7:989–1000. 19043450 10.1038/nrd2658

203. Oda E Ohki R Murasawa H Nemoto J Shibue T Yamashita T Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis Science 2000 288 1053 8 10.1126/science.288.5468.1053 10807576 Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000;288:1053–8. 10807576 10.1126/science.288.5468.1053

204. Yu J Zhang L PUMA, a potent killer with or without p53 Oncogene 2008 27 Suppl 1 S71 83 10.1038/onc.2009.45 19641508 PMC2860432 Yu J, Zhang L. PUMA, a potent killer with or without p53. Oncogene. 2008;27(Suppl 1):S71–83. 19641508 10.1038/onc.2009.45 PMC2860432

205. Roberts AW Davids MS Pagel JM Kahl BS Puvvada SD Gerecitano JF Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia N Engl J Med 2016 374 311 22 10.1056/NEJMoa1513257 26639348 PMC7107002 Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374:311–22. 26639348 10.1056/NEJMoa1513257 PMC7107002

206. Delbridge AR Strasser A The BCL-2 protein family, BH3-mimetics and cancer therapy Cell Death Differ 2015 22 1071 80 10.1038/cdd.2015.50 25952548 PMC4572872 Delbridge AR, Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 2015;22:1071–80. 25952548 10.1038/cdd.2015.50 PMC4572872

207. Ashkenazi A Targeting the extrinsic apoptosis pathway in cancer Cytokine Growth Factor Rev 2008 19 325 31 10.1016/j.cytogfr.2008.04.001 18495520 Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev. 2008;19:325–31. 18495520 10.1016/j.cytogfr.2008.04.001

208. Lemke J von Karstedt S Zinngrebe J Walczak H Getting TRAIL back on track for cancer therapy Cell Death Differ 2014 21 1350 64 10.1038/cdd.2014.81 24948009 PMC4131183 Lemke J, von Karstedt S, Zinngrebe J, Walczak H. Getting TRAIL back on track for cancer therapy. Cell Death Differ. 2014;21:1350–64. 24948009 10.1038/cdd.2014.81 PMC4131183

209. Fischer K Al-Sawaf O Bahlo J Fink AM Tandon M Dixon M Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions N Engl J Med 2019 380 2225 36 10.1056/NEJMoa1815281 31166681 Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019;380:2225–36. 31166681 10.1056/NEJMoa1815281

210. Seymour JF Kipps TJ Eichhorst B Hillmen P D’Rozario J Assouline S Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia N Engl J Med 2018 378 1107 20 10.1056/NEJMoa1713976 29562156 Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S, et al. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2018;378:1107–20. 29562156 10.1056/NEJMoa1713976

211. Stilgenbauer S Eichhorst B Schetelig J Coutre S Seymour JF Munir T Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study Lancet Oncol 2016 17 768 78 10.1016/S1470-2045(16)30019-5 27178240 Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–78. 27178240 10.1016/S1470-2045(16)30019-5

212. Ashkenazi A Targeting death and decoy receptors of the tumour-necrosis factor superfamily Nat Rev Cancer 2002 2 420 30 10.1038/nrc821 12189384 Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002;2:420–30. 12189384 10.1038/nrc821

213. Kelley SK Ashkenazi A Targeting death receptors in cancer with Apo2L/TRAIL Curr Opin Pharmacol 2004 4 333 9 10.1016/j.coph.2004.02.006 15251125 Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol. 2004;4:333–9. 15251125 10.1016/j.coph.2004.02.006

214. Sayers TJ Targeting the extrinsic apoptosis signaling pathway for cancer therapy Cancer Immunol Immunother 2011 60 1173 80 10.1007/s00262-011-1008-4 21626033 PMC11028721 Sayers TJ. Targeting the extrinsic apoptosis signaling pathway for cancer therapy. Cancer Immunol Immunother. 2011;60:1173–80. 21626033 10.1007/s00262-011-1008-4 PMC11028721

215. el-Deiry WS Tokino T Velculescu VE Levy DB Parsons R Trent JM WAF1, a potential mediator of p53 tumor suppression Cell 1993 75 817 25 10.1016/0092-8674(93)90500-P 8242752 el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–25. 8242752 10.1016/0092-8674(93)90500-p

216. Harper JW Adami GR Wei N Keyomarsi K Elledge SJ The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases Cell 1993 75 805 16 10.1016/0092-8674(93)90499-G 8242751 Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993;75:805–16. 8242751 10.1016/0092-8674(93)90499-g

217. Malumbres M Barbacid M Cell cycle, CDKs and cancer: a changing paradigm Nat Rev Cancer 2009 9 153 66 10.1038/nrc2602 19238148 Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66. 19238148 10.1038/nrc2602

218. Sherr CJ McCormick F The RB and p53 pathways in cancer Cancer Cell 2002 2 103 12 10.1016/S1535-6108(02)00102-2 12204530 Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002;2:103–12. 12204530 10.1016/s1535-6108(02)00102-2

219. Finn RS Crown JP Lang I Boer K Bondarenko IM Kulyk SO The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study Lancet Oncol 2015 16 25 35 10.1016/S1470-2045(14)71159-3 25524798 Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25–35. 25524798 10.1016/S1470-2045(14)71159-3

220. O’Leary B Finn RS Turner NC Treating cancer with selective CDK4/6 inhibitors Nat Rev Clin Oncol 2016 13 417 30 10.1038/nrclinonc.2016.26 27030077 O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417–30. 27030077 10.1038/nrclinonc.2016.26

221. Finn RS Martin M Rugo HS Jones S Im SA Gelmon K Palbociclib and Letrozole in Advanced Breast Cancer N Engl J Med 2016 375 1925 36 10.1056/NEJMoa1607303 27959613 Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016;375:1925–36. 27959613 10.1056/NEJMoa1607303

222. Thu KL Soria-Bretones I Mak TW Cescon DW Targeting the cell cycle in breast cancer: towards the next phase Cell Cycle 2018 17 1871 85 10.1080/15384101.2018.1502567 30078354 PMC6152498 Thu KL, Soria-Bretones I, Mak TW, Cescon DW. Targeting the cell cycle in breast cancer: towards the next phase. Cell Cycle. 2018;17:1871–85. 30078354 10.1080/15384101.2018.1502567 PMC6152498

223. Cortez MA, Ivan C, Valdecanas D, Wang X, Peltier HJ, Ye Y et al. PDL1 Regulation by p53 via miR-34. J Natl Cancer Inst 2016;108. 10.1093/jnci/djv303 PMC4862407 26577528

224. Rahnamoun H Lu H Duttke SH Benner C Glass CK Lauberth SM Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling Nat Commun 2017 8 754 10.1038/s41467-017-01117-y 28963538 PMC5622043 Rahnamoun H, Lu H, Duttke SH, Benner C, Glass CK, Lauberth SM. Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling. Nat Commun. 2017;8:754. 28963538 10.1038/s41467-017-01117-y PMC5622043

225. Rizvi NA Hellmann MD Snyder A Kvistborg P Makarov V Havel JJ Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer Science 2015 348 124 8 10.1126/science.aaa1348 25765070 PMC4993154 Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8. 25765070 10.1126/science.aaa1348 PMC4993154

226. Assoun S Theou-Anton N Nguenang M Cazes A Danel C Abbar B Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer Lung Cancer 2019 132 65 71 10.1016/j.lungcan.2019.04.005 31097096 Assoun S, Theou-Anton N, Nguenang M, Cazes A, Danel C, Abbar B, et al. Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer. Lung Cancer. 2019;132:65–71. 31097096 10.1016/j.lungcan.2019.04.005

227. Biton J Mansuet-Lupo A Pecuchet N Alifano M Ouakrim H Arrondeau J STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma Clin Cancer Res 2018 TP53 5710 23 10.1158/1078-0432.CCR-18-0163 29764856 Biton J, Mansuet-Lupo A, Pecuchet N, Alifano M, Ouakrim H, Arrondeau J, et al. STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma. Clin Cancer Res. 2018;TP53:24: 5710–23. 10.1158/1078-0432.CCR-18-0163 29764856

228. Ghosh M Saha S Bettke J Nagar R Parrales A Iwakuma T Mutant p53 suppresses innate immune signaling to promote tumorigenesis Cancer Cell 2021 39 494 508 10.1016/j.ccell.2021.01.003 33545063 PMC8044023 Ghosh M, Saha S, Bettke J, Nagar R, Parrales A, Iwakuma T, et al. Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cancer Cell. 2021;39:494–508. e495. 33545063 10.1016/j.ccell.2021.01.003 PMC8044023

229. Liu N Jiang X Guo L Zhang C Jiang M Sun Z Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway Int J Biol Sci 2022 18 2419 38 10.7150/ijbs.67200 35414774 PMC8990467 Liu N, Jiang X, Guo L, Zhang C, Jiang M, Sun Z, et al. Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway. Int J Biol Sci. 2022;18:2419–38. 35414774 10.7150/ijbs.67200 PMC8990467

230. Zhou X Santos GS Zhan Y Oliveira MMS Rezaei S Singh M Mutant p53 gain of function mediates cancer immune escape that is counteracted by APR-246 Br J Cancer 2022 127 2060 71 10.1038/s41416-022-01971-8 36138076 PMC9681866 Zhou X, Santos GS, Zhan Y, Oliveira MMS, Rezaei S, Singh M, et al. Mutant p53 gain of function mediates cancer immune escape that is counteracted by APR-246. Br J Cancer. 2022;127:2060–71. 36138076 10.1038/s41416-022-01971-8 PMC9681866

231. Dameron KM Volpert OV Tainsky MA Bouck N Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1 Science 1994 265 1582 4 10.1126/science.7521539 7521539 Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science. 1994;265:1582–4. 7521539 10.1126/science.7521539

232. Mukhopadhyay D Tsiokas L Sukhatme VP Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression Cancer Res 1995 55 6161 5 8521408 Mukhopadhyay D, Tsiokas L, Sukhatme VP. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 1995;55:6161–5. 8521408

233. Ravi R Mookerjee B Bhujwalla ZM Sutter CH Artemov D Zeng Q Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha Genes Dev 2000 14 34 44 10.1101/gad.14.1.34 10640274 PMC316350 Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 2000;14:34–44. 10640274 PMC316350

234. Fontemaggi G Dell’Orso S Trisciuoglio D Shay T Melucci E Fazi F The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis Nat Struct Mol Biol 2009 16 1086 93 10.1038/nsmb.1669 19783986 Fontemaggi G, Dell’Orso S, Trisciuoglio D, Shay T, Melucci E, Fazi F, et al. The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis. Nat Struct Mol Biol. 2009;16:1086–93. 19783986 10.1038/nsmb.1669

235. Teodoro JG Evans SK Green MR Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome J Mol Med (Berl) 2007 85 1175 86 10.1007/s00109-007-0221-2 17589818 Teodoro JG, Evans SK, Green MR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med (Berl). 2007;85:1175–86. 17589818 10.1007/s00109-007-0221-2

236. Schwaederle M Lazar V Validire P Hansson J Lacroix L Soria JC VEGF-A Expression Correlates with TP53 Mutations in Non-Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy Cancer Res 2015 75 1187 90 10.1158/0008-5472.CAN-14-2305 25672981 Schwaederle M, Lazar V, Validire P, Hansson J, Lacroix L, Soria JC, et al. VEGF-A Expression Correlates with TP53 Mutations in Non-Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy. Cancer Res. 2015;75:1187–90. 25672981 10.1158/0008-5472.CAN-14-2305

237. Thiel KW Devor EJ Filiaci VL Mutch D Moxley K Alvarez Secord A TP53 Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study J Clin Oncol 2022 40 3289 300 10.1200/JCO.21.02506 35658479 PMC9553389 Thiel KW, Devor EJ, Filiaci VL, Mutch D, Moxley K, Alvarez Secord A, et al. TP53 Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol. 2022;40:3289–300. 35658479 10.1200/JCO.21.02506 PMC9553389

238. Wheler JJ Janku F Naing A Li Y Stephen B Zinner R TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics Mol Cancer Ther 2016 15 2475 85 10.1158/1535-7163.MCT-16-0196 27466356 Wheler JJ, Janku F, Naing A, Li Y, Stephen B, Zinner R, et al. TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics. Mol Cancer Ther. 2016;15:2475–85. 27466356 10.1158/1535-7163.MCT-16-0196

239. Levine AJ p53: 800 million years of evolution and 40 years of discovery Nat Rev Cancer 2020 20 471 80 10.1038/s41568-020-0262-1 32404993 Levine AJ. p53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer. 2020;20:471–80. 32404993 10.1038/s41568-020-0262-1

240. Soussi T Wiman KG Shaping genetic alterations in human cancer: the p53 mutation paradigm Cancer Cell 2007 12 303 12 10.1016/j.ccr.2007.10.001 17936556 Soussi T, Wiman KG. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell. 2007;12:303–12. 17936556 10.1016/j.ccr.2007.10.001

241. Lowe SW Ruley HE Jacks T Housman DE p53-dependent apoptosis modulates the cytotoxicity of anticancer agents Cell 1993 74 957 67 10.1016/0092-8674(93)90719-7 8402885 Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74:957–67. 8402885 10.1016/0092-8674(93)90719-7

242. Jackson JG Lozano G The mutant p53 mouse as a pre-clinical model Oncogene 2013 32 4325 30 10.1038/onc.2012.610 23318424 Jackson JG, Lozano G. The mutant p53 mouse as a pre-clinical model. Oncogene. 2013;32:4325–30. 23318424 10.1038/onc.2012.610

243. Vu BT Dominique R Fahr BJ Li HH Fry DC Xu L Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development ACS Med Chem Lett 2025 16 34 9 10.1021/acsmedchemlett.4c00379 39811143 PMC11726359 Vu BT, Dominique R, Fahr BJ, Li HH, Fry DC, Xu L, et al. Discovery of Rezatapopt (PC14586), a First-in-Class, Small-Molecule Reactivator of p53 Y220C Mutant in Development. ACS Med Chem Lett. 2025;16:34–9. 39811143 10.1021/acsmedchemlett.4c00379 PMC11726359

244. Hellmann MD Ciuleanu TE Pluzanski A Lee JS Otterson GA Audigier-Valette C Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden N Engl J Med 2018 378 2093 104 10.1056/NEJMoa1801946 29658845 PMC7193684 Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378:2093–104. 29658845 10.1056/NEJMoa1801946 PMC7193684

245. Bryant HE Schultz N Thomas HD Parker KM Flower D Lopez E Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase Nature 2005 434 913 7 10.1038/nature03443 15829966 Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–7. 15829966 10.1038/nature03443

246. Farmer H McCabe N Lord CJ Tutt AN Johnson DA Richardson TB Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy Nature 2005 434 917 21 10.1038/nature03445 15829967 Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21. 15829967 10.1038/nature03445

247. Lord CJ Ashworth A PARP inhibitors: Synthetic lethality in the clinic Science 2017 355 1152 8 10.1126/science.aam7344 28302823 PMC6175050 Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355:1152–8. 28302823 10.1126/science.aam7344 PMC6175050

248. Duffy MJ Synnott NC Crown J Mutant p53 as a target for cancer treatment Eur J Cancer 2017 83 258 65 10.1016/j.ejca.2017.06.023 28756138 Duffy MJ, Synnott NC, Crown J. Mutant p53 as a target for cancer treatment. Eur J Cancer. 2017;83:258–65. 28756138 10.1016/j.ejca.2017.06.023

249. Khoo KH Verma CS Lane DP Drugging the p53 pathway: understanding the route to clinical efficacy Nat Rev Drug Discov 2014 13 217 36 10.1038/nrd4236 24577402 Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014;13:217–36. 24577402 10.1038/nrd4236

250. Sabapathy K Lane DP Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others Nat Rev Clin Oncol 2018 15 13 30 10.1038/nrclinonc.2017.151 28948977 Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15:13–30. 28948977 10.1038/nrclinonc.2017.151

251. Haronikova L Bonczek O Zatloukalova P Kokas-Zavadil F Kucerikova M Coates PJ Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them? Cell Mol Biol Lett 2021 26 53 10.1186/s11658-021-00293-6 34911439 PMC8903693 Haronikova L, Bonczek O, Zatloukalova P, Kokas-Zavadil F, Kucerikova M, Coates PJ, et al. Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them? Cell Mol Biol Lett. 2021;26:53. 34911439 10.1186/s11658-021-00293-6 PMC8903693

252. Bauer MR Joerger AC Fersht AR 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells Proc Natl Acad Sci U S A 2016 113 E5271 5280 10.1073/pnas.1610421113 27551077 PMC5018792 Bauer MR, Joerger AC, Fersht AR. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells. Proc Natl Acad Sci U S A. 2016;113:E5271–5280. 27551077 10.1073/pnas.1610421113 PMC5018792

253. Bykov VJ Wiman KG Mutant p53 reactivation by small molecules makes its way to the clinic FEBS Lett 2014 588 2622 7 10.1016/j.febslet.2014.04.017 24768524 Bykov VJ, Wiman KG. Mutant p53 reactivation by small molecules makes its way to the clinic. FEBS Lett. 2014;588:2622–7. 24768524 10.1016/j.febslet.2014.04.017

254. Zhou X Singh M Sanz Santos G Guerlavais V Carvajal LA Aivado M Pharmacologic Activation of p53 Triggers Viral Mimicry Response Thereby Abolishing Tumor Immune Evasion and Promoting Antitumor Immunity Cancer Discov 2021 11 3090 105 10.1158/2159-8290.CD-20-1741 34230007 PMC9414294 Zhou X, Singh M, Sanz Santos G, Guerlavais V, Carvajal LA, Aivado M, et al. Pharmacologic Activation of p53 Triggers Viral Mimicry Response Thereby Abolishing Tumor Immune Evasion and Promoting Antitumor Immunity. Cancer Discov. 2021;11:3090–105. 34230007 10.1158/2159-8290.CD-20-1741 PMC9414294

255. Lino CA Harper JC Carney JP Timlin JA Delivering CRISPR: a review of the challenges and approaches Drug Deliv 2018 25 1234 57 10.1080/10717544.2018.1474964 29801422 PMC6058482 Lino CA, Harper JC, Carney JP, Timlin JA. Delivering CRISPR: a review of the challenges and approaches. Drug Deliv. 2018;25:1234–57. 29801422 10.1080/10717544.2018.1474964 PMC6058482

256. Zhen S Hua L Takahashi Y Narita S Liu YH Li Y In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9 Biochem Biophys Res Commun 2014 450 1422 6 10.1016/j.bbrc.2014.07.014 25044113 Zhen S, Hua L, Takahashi Y, Narita S, Liu YH, Li Y. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9. Biochem Biophys Res Commun. 2014;450:1422–6. 25044113 10.1016/j.bbrc.2014.07.014

257. Leijen S van Geel RM Sonke GS de Jong D Rosenberg EH Marchetti S Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months J Clin Oncol 2016 34 4354 61 10.1200/JCO.2016.67.5942 27998224 Leijen S, van Geel RM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, et al. Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months. J Clin Oncol. 2016;34:4354–61. 27998224 10.1200/JCO.2016.67.5942

258. O’Connor MJ Targeting the DNA Damage Response in Cancer Mol Cell 2015 60 547 60 10.1016/j.molcel.2015.10.040 26590714 O’Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell. 2015;60:547–60. 26590714 10.1016/j.molcel.2015.10.040

259. Jumper J Evans R Pritzel A Green T Figurnov M Ronneberger O Highly accurate protein structure prediction with AlphaFold Nature 2021 596 583 9 10.1038/s41586-021-03819-2 34265844 PMC8371605 Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–9. 34265844 10.1038/s41586-021-03819-2 PMC8371605

260. Sharma V Singh A Chauhan S Sharma PK Chaudhary S Sharma A Role of Artificial Intelligence in Drug Discovery and Target Identification in Cancer Curr Drug Deliv 2024 21 870 86 10.2174/1567201821666230905090621 37670704 Sharma V, Singh A, Chauhan S, Sharma PK, Chaudhary S, Sharma A, et al. Role of Artificial Intelligence in Drug Discovery and Target Identification in Cancer. Curr Drug Deliv. 2024;21:870–86. 37670704 10.2174/1567201821666230905090621

261. Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol 2017; 2017. 10.1200/PO.17.00011 PMC5586540 28890946

262. Mandelker D Zhang L Kemel Y Stadler ZK Joseph V Zehir A Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing JAMA 2017 318 825 35 10.1001/jama.2017.11137 28873162 PMC5611881 Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. 2017;318:825–35. 28873162 10.1001/jama.2017.11137 PMC5611881

263. Blandino G Levine AJ Oren M Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy Oncogene 1999 18 477 85 10.1038/sj.onc.1202314 9927204 Blandino G, Levine AJ, Oren M. Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene. 1999;18:477–85. 9927204 10.1038/sj.onc.1202314

264. Doudna JA Charpentier E Genome editing. The new frontier of genome engineering with CRISPR-Cas9 Science 2014 346 1258096 10.1126/science.1258096 25430774 Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346:1258096. 25430774 10.1126/science.1258096

265. Hock AK Vousden KH The role of ubiquitin modification in the regulation of p53 Biochim Biophys Acta 2014 1843 137 49 10.1016/j.bbamcr.2013.05.022 23742843 Hock AK, Vousden KH. The role of ubiquitin modification in the regulation of p53. Biochim Biophys Acta. 2014;1843:137–49. 23742843 10.1016/j.bbamcr.2013.05.022

266. Marine JC Lozano G Mdm2-mediated ubiquitylation: p53 and beyond Cell Death Differ 2010 17 93 102 10.1038/cdd.2009.68 19498444 Marine JC, Lozano G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 2010;17:93–102. 19498444 10.1038/cdd.2009.68

267. Wade M Li YC Wahl GM MDM2, MDMX and p53 in oncogenesis and cancer therapy Nat Rev Cancer 2013 13 83 96 10.1038/nrc3430 23303139 PMC4161369 Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13:83–96. 23303139 10.1038/nrc3430 PMC4161369