Emerging Targets in Non-Small Cell Lung Cancer.

1. Introduction

Lung cancer remains the leading cause of cancer-related death globally. The most common type of lung cancer is non-small cell lung cancer (NSCLC) with adenocarcinoma being the most common subtype. Lung cancer has been traditionally classified by histology and historically treated with chemotherapy as the mainstay of treatment. The identification of targetable oncogenic genomic alterations has significantly transformed the treatment paradigm for advanced or metastatic non-small cell lung cancer (NSCLC). Over the last two decades, several targets have been identified in lung adenocarcinoma (LUAD) including EGFR exon 19 deletion and L858R mutations, ALK , ROS1 , and NTRK re-arrangements, RET rearrangements, BRAF V600E mutations, and MET exon 14 alterations, all of which have approved therapies available [ 1 , 2 ]. These targeted therapies have resulted in better outcomes and quality of life compared to chemotherapy in patients with tumors that harbor the oncogenic drivers. Recently, the spectrum of actionable genomic alterations (AGA) in LUAD has broadened to include KRAS G12C and HER2 with the approval of new therapies [ 3 , 4 , 5 , 6 ]. Emerging molecular drivers continue to present promising therapeutic targets, including mutations in KRAS, RAF/MEK, HER3, Nectin-4, folate receptor alpha, ITGB6, and PRMT5 ( Figure 1 ). This review aims to summarize the emerging therapeutic targets for NSCLC, elucidating their molecular pathways, therapeutic potentials, and ongoing trials.

2. KRAS

2.1. Molecular Pathway

RAS genes, including Kirsten Rat Sarcoma viral oncogene ( KRAS ), are proto-oncogenes encoding intracellular guanine nucleotide-binding proteins that belong to the GTPase family. RAS proteins are composed of two major domains: a catalytic domain called the G-domain, which binds guanine nucleotides and activates signaling, and a hypervariable region, which determines where the RAS proteins are localized on the cell membrane to perform their signaling function [ 7 ]. During signal transduction, RAS proteins act as molecular switches, cycling between on and off states. The guanosine triphosphate (GTP)-bound state is the active form while the guanosine diphosphate (GDP)-bound state is the inactive form. RAS-GTP binding acquires an altered conformation in the G-domain and activates a series of multiple signaling cascades [ 8 , 9 , 10 ]. Some of these pathways include RAF/MEK/ERK, PI3K/AKT/mTOR, RalA/B, and TIAM1/RAC1, which regulate cell proliferation, differentiation, and apoptosis. Approximately 90% of KRAS mutations are detected in exon 2. The most frequent mutations are the nucleotide substitutions in 12 codons of KRAS exon 2: p.G12C, p.G12D, and p.G12V [ 11 ]. These mutations impair the conversion from GTP-bound to GDP-bound state and lead to constitutive activation of downstream signaling independent of activation of upstream proteins [ 12 ]. KRAS may also play a role in modulating the tumor microenvironment to promote tumor progression as seen in preclinical studies in colorectal cancer. KRAS mutations have been associated with decreased major histocompatibility class I expression, upregulation of PD-L1, and promotion of an immunosuppressive immune cell population as myeloid-derived suppressor cells [ 13 ].

2.2. Clinical Characteristics

KRAS mutations are the most frequently detected gain-of-function mutations found in LUAD and have been historically considered “undruggable” [ 14 ]. KRAS mutations have been associated with a poor prognosis compared to KRAS wild-type tumors and carry an association with tobacco use [ 15 ]. The most frequent somatic mutation in NSCLC is KRAS G12C [ 16 ]. The KRAS G12C variant occurs more commonly in Western as opposed to Asian patients. Interestingly, there are significant differences in the distribution of KRAS somatic mutations by sex within the same ethnic groups, with the KRAS G12C variant occurring more frequently in White female patients than in White male patients and more frequently in Asian male patients than in Asian female patients with NSCLC [ 17 ].

2.3. Treatment

Due to the intrinsic characteristics of KRAS proteins including their lack of binding sites, small dimensions, and high affinity for GTP/GDP, KRAS remained a challenging therapeutic target for decades [ 18 ]. However, recent breakthroughs have led to the discovery of small molecules that bind covalently to mutant KRAS leading to subsequent formation of a new pocket in the switch-II region within the KRAS protein [ 19 ].

The identification of this allosteric switch II pocket has prompted the search for pharmacologic agents that target mutant forms of KRAS, particularly KRAS G12C. In the CodeBreak100 study, sotorasib showed an objective response rate (ORR) of 41% and progression-free survival (PFS) of 6.3 months in patients with advanced NSCLC [ 20 ]. In a phase III randomized trial of sotorasib versus docetaxel in previously treated patients with advanced NSCLC, sotorasib demonstrated increased PFS and a more favorable safety profile, however without a significant improvement in overall survival (OS) [ 21 ]. Similar results were reported with adagrasib from the phase 1 KRYSTAL-1 study where adagrasib demonstrated an ORR of 42.9% and PFS of 6.5 months [ 22 ]. The KRYSTAL-12 study randomized previously treated patients with advanced NSCLC to adagrasib and docetaxel, and similarly showed improvement in PFS and ORR with adagrasib [ 23 ]. The US Food and Drug Administration (FDA) granted accelerated approval for sotorasib in 2021 and adagrasib in 2022 for the treatment of previously treated patients with advanced NSCLC harboring KRAS G12C mutations based on these studies.

2.4. Novel Strategies to Target KRAS

KRAS G12C inhibitors: Newer KRAS G12C selective inhibitors intended to improve upon first-in-class inhibitors (sotorasib and adagrasib) are currently in clinical trials. Glecirasib (JAB-21822) exhibited potent anti-tumor efficacy both in vitro and in vivo as a single agent in preclinical models [ 24 ]. In a phase 2 single-arm trial in China evaluating 119 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC who had progressed on platinum-based chemoimmunotherapy, glecirasib demonstrated an ORR of 47% and median PFS of 8.2 months (95% CI, 5.5–13.1) [ 25 ]. Glecirasib was well-tolerated with no dose-limiting toxicities (DLTs); the most common adverse effects were anemia, liver function abnormalities, and proteinuria. Divarasib (GDC-6036) demonstrated greater potency and selectivity for KRAS G12C in vitro compared to sotorasib and adagrasib in preclinical studies [ 26 ]. Divarasib demonstrated an ORR of 53.4% and PFS of 13.1 months in patients with NSCLC [ 27 ]. Treatment-related adverse events (TRAEs) occurred in 93% of patients, the majority of which (94%) were grade 1 or 2 severity. The most common TRAEs were nausea, diarrhea, and vomiting. Olomorasib (LY3537982) showed a range of anti-tumor activity from complete regression to significant tumor growth inhibition in xenograft models harboring KRAS G12C mutation [ 28 ]. Preliminary clinical data of olomorasib have reported an ORR of 60% and a favorable safety profile with absence of high-grade liver toxicity in patients with treatment-naïve KRAS G12C NSCLC [ 29 ] ( NCT04956640 ) and have subsequently prompted the phase III trial SUNRAY-01 studying its combination with pembrolizumab with or without platinum-based chemotherapy based on PD-L1 expression level as the first-line treatment in patients with KRAS G12C-mutant advanced NSCLC ( NCT06119581 ) [ 30 ]. Preclinical investigation of opnurasib (JDQ443) showed potent and selective anti-tumor activity in KRAS G12C cell lines and comparable efficacy to sotorasib [ 31 ]. Phase I data of opnurasib showed an ORR of 57% and DCR of 93% among 14 patients receiving the recommended dose of 200 mg twice daily ( NCT04699188 ) [ 32 ]. A total of 71.4% of patients experienced a TRAE of any grade, with 7.1% of grade 3 and no grade 4–5 events at any dose level. The most common TRAEs were fatigue, edema, diarrhea, nausea, vomiting, and peripheral neuropathy. Opnurasib is currently being evaluated in a phase III randomized trial compared to docetaxel in previously treated patients with advanced NSCLC ( NCT05132075 ) [ 33 ]. It is also being studied in a phase I/II trial in combination with the SHP2 inhibitor TNO155 or anti-PD1 antibody tislelizumab in patients with advanced KRAS G12C-mutated solid tumors ( NCT04699188 ) [ 32 ]. Garsorasib (D-1553) demonstrated strong tumor growth inhibition with excellent central nervous system penetration preclinically [ 34 ]. Garsorasib demonstrated 40.5% ORR, 91.9% DCR, and 8.2 months median PFS in a phase I trial of patients in China with locally advanced or metastatic KRAS G12C-mutant NSCLC who were refractory to or intolerant of standard chemoimmunotherapy [ 35 ]. Across all doses of garsorasib, 95% of patients had TRAEs, most of which (57%) were grade 1 or 2 in severity. The most common TRAEs were liver function abnormalities, diarrhea, nausea, and vomiting. A total of 31% of patients required a dose interruption or reduction. Other KRAS G12C inhibitors such as ASP2453 are in preclinical development.

KRAS G12D inhibitors : The identification of small-molecule compounds that target KRAS-mutant proteins have inspired the rapid development of selective KRAS G12D inhibitors, which form salt bridges to bind to KRAS G12D in both its active and inactive states. The KRAS G12D inhibitor MRTX1133 has demonstrated potent in vitro and in vivo antitumor efficacy against KRAS G12D-mutant cancer cells in preclinical studies and is now being investigated in a phase I/II multiple expansion cohort trial in patients with advanced solid tumors harboring a KRAS G12D mutation ( NCT05737706 ). Preclinical data have also suggested synergy with immunotherapy, as T-cells may augment the extent and duration of antitumor effect. The use of MRTX1133 in combination with checkpoint inhibitors targeting CTLA-4 or PD-1 resulted in enhanced tumor regression in xenograft models of pancreatic adenocarcinoma [ 36 ]. HRS-4642 exhibited anti-tumor efficacy in preclinical models as well as a disease control rate (DCR) of 94.4% in a phase I trial enrolling patients with advanced solid tumors harboring KRAS G12D mutations including 10 patients with NSCLC [ 37 ]. A third of the patients experienced a TRAE of grade 3 or higher, including hypercholesterolemia, increased lipase, and anemia. No treatment discontinuations or deaths due to TRAEs were reported. RMC-9805 (Revolution Medicines, Redwood City, CA, USA) and INCB161734 (Incyte) are other selective KRAS G12D inhibitors with promising preclinical results [ 38 , 39 ]. Their potential benefit as single agents or in combination with other anticancer therapies for patients with advanced or metastatic solid tumors with KRAS G12D mutation are under investigation in ongoing phase I trials ( NCT06040541 , NCT06179160 ).

KRAS degraders : Complementary therapeutic strategies aimed at targeting KRAS include KRAS degraders, which utilize cell degradation machinery to selectively eliminate mutant KRAS protein. Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that recruit a protein of interest, such as KRAS, to the cell’s ubiquitin-proteasome system for degradation [ 40 ]. ASP3082 (Astellas Pharma) is a PROTAC that binds to KRAS G12D and E3 ubiquitin ligase, leading to selective KRAS G12D protein degradation and growth inhibitory activity in KRAS G12D-mutated cancer cells while sparing KRAS wild-type cancer cells [ 41 ]. Its safety and tolerability is currently being studied in patients with NSCLC, colorectal cancer, pancreatic cancer, and other solid tumors with documented KRAS G12D mutations in a phase I trial [ 42 ].

Pan-RAS inhibitors: Pan-RAS inhibitors are designed to target multiple RAS isoforms at once. RMC-6236 (Revolution Medicines, NCT05379985 ) is a noncovalent inhibitor of the active GTP-bound state of several RAS variants. In vivo evaluations of RMC-6236 resulted in significant and durable tumor regression across multiple tumor types, particularly in NSCLC and pancreatic adenocarcinomas harboring KRAS glycine-12 substitutions ( KRAS G12X) [ 43 ]. Preliminary phase I data of RMC-6236 demonstrated an ORR of 38% and DCR of 85% in 40 patients with previously treated advanced KRAS G12X-mutant NSCLC [ 44 ]. Across both NSCLC and pancreatic adenocarcinoma cohorts, the most common toxicities observed with RMC-6236 were rash, nausea, diarrhea, vomiting, stomatitis, and fatigue, nearly all of which were grade 1 or 2. QTX3034 (Quanta Therapeutics), RSC-1255 (RasCal Therapeutics), and YL-17231 (TEB-17231, Shanghai YingLi Pharmaceutical Co., Shanghai, China) are other pan-RAS inhibitors that have also demonstrated durable inhibition of KRAS signaling in vivo and tumor growth in vitro [ 45 , 46 , 47 ]. These agents are currently being studied in early-phase clinical trials of advanced solid tumors with KRAS mutations ( NCT06227377 , NCT04678648 , NCT06078800 ) [ 48 ]. A comprehensive list of novel agents targeting KRAS is provided in Table 1 .

Immunologic approaches: Other therapies targeting KRAS in development include neoantigen vaccines and adoptive cellular therapies. KRAS peptide vaccines are an emerging approach aimed at eliciting an immune response against cancer cells that harbor KRAS mutations. TG01 (Targovax), a peptide vaccine derived from KRAS-mutant proteins, has been tested in phase I trials of patients with multiple myeloma [ 49 ] and resected pancreatic cancer [ 50 , 51 ]. Efforts to expand the application of KRAS vaccines to NSCLC are ongoing. TG01 will be studied in a phase II trial in combination with daratumumab and nivolumab in patients with advanced refractory RAS-mutated NSCLC and pancreatic ductal cancer ( NCT06015724 ). ELI-002 is a vaccine comprising lymph node-targeted amphiphile-modified G12D and G12R-mutant KRAS peptides together with a CpG oligonucleotide adjuvant. Preclinical data have shown increased cytotoxic T-cell responses and tumor clearance with ELI-002 [ 52 , 53 ]. The AMPLIFY-201 trial is a first-in-human phase I study of ELI-002 as treatment for patients with KRAS -mutated pancreatic ductal cancer and other solid tumors. Preliminary results from the trial included patients with KRAS G12D- or G12R-mutated pancreatic and colorectal cancer following surgery and chemotherapy, and demonstrated serum tumor biomarker reduction and notable immune responses in 80% of patients [ 54 ]. The safety and efficacy of ELI-002 will be further investigated in patients with high relapse risk KRAS -driven solid tumor types in the phase II AMPLIFY-7P trial ( NCT05726864 ). Similarly, mRNA vaccines, which encode the mutant KRAS protein to induce an immune response, are being investigated as monotherapy or in combination with immune checkpoint inhibitors in KRAS -mutant advanced solid tumors including NSCLC ( NCT03948763 , NCT05202561 ) [ 55 ]. Other novel immunologic approaches like adoptive cellular therapies may offer patients a more personalized strategy for the management of NSCLC. These involve the generation of artificial T-cells or infusion of ex vivo expanded endogenous T-cells to improve therapeutic responses by enhancing tumor recognition and overcoming tumor-mediated immune suppression [ 56 ]. It remains to be seen whether the success of T-cell therapies that have revolutionized the treatment landscape of hematologic malignancies can be translated to solid tumors. The use of autologous engineered T-cells, tumor-infiltrating lymphocyte therapy, and T-cell receptor therapy have been introduced as potential treatments in NSCLC, though they remain in the early stages of development [ 56 , 57 ].

3. RAS/MEK

3.1. Molecular Pathway

BRAF mutations are diverse, with each mutation producing functionally distinct BRAF proteins. The altered BRAF proteins engage and activate the MAPK pathways in various ways. The initiation of the MAPK pathway will lead to RAS binding to GTP (RAS-GTP). Activated RAS triggers activation of the RAF family of kinases, which translocates to the cell membrane and forms homo- or heterodimers. Active RAF dimers autophosphorylate their activation loops and subsequently activate MEK dimers which in turn phosphorylate and activate ERK. Phosphorylated ERK then activates transcription factors which leads to cell growth, proliferation, differentiation, and survival.

Mutations in the RAF kinase domains lead to constitutive activation of BRAF. A single-point mutation in the V600 position of the activation loop represents >90% of all cancer-related RAF mutations [ 58 ]. BRAF V600E mutation leads to constitutive RAF activation independent of RAS signaling and consequently increased tumor cell survival, proliferation, angiogenesis, and metastasis via the ERK signaling pathway. Importantly, with activation of phosphorylated ERK, negative feedback to upstream RAS and receptor tyrosine kinases does not allow for dimerization. Two regulatory elements of BRAF are the α C-helix and aspartate-phenylalanine-glycine (DFG) motif. Treatment with RAF inhibitors causes allosteric structural changes that lock these elements into specific conformations.

3.2. Clinical Characteristics

Mutations in the mitogen-activated protein kinase (MAPK) pathway are implicated in the tumorigenesis of NSCLC. It is comprised of the kinases RAS, RAF, MEK, and ERK. Downstream receptors of the pathway, including RAF and MEK, have been studied as potential targets and offer promising therapeutic opportunities in NSCLC. BRAF mutations are identified in 6–8% of all cancers and in 1–2% of NSCLC [ 59 ]. The most common activating BRAF mutation is a point mutation in codon 600 (V600E) and is found almost exclusively in LUAD. There is no clear association of BRAF mutation with age, ethnicity, or sex [ 60 ]. Epidemiologic patterns are not clearly identifiable since BRAF mutation occurs in a small fraction of patients with advanced NSCLC [ 61 ]. Conflicting studies have reported smoking history to be or not be associated with BRAF V600E or non- V600E mutations [ 62 ]. Thus, all patients with advanced NSCLC, regardless of smoking history, should undergo broad molecular testing. BRAF mutation in NSCLC is often associated with increased programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) [ 63 ]. However, the prognostic implications of BRAF mutation in NSCLC are inconclusive.

3.3. Treatments

Selective BRAF inhibitors: Vemurafenib, dabrafenib, and encorafenib were developed as highly selective BRAF inhibitors. They specifically bind to the active conformation of the BRAF kinase, occupying the ATP binding pocket and stabilizing the active conformation, leading to the potent inhibition of BRAF V600. Encorafenib exhibits activity against BRAF V600E, BRAF V600K, and wild-type BRAF . Dabrafenib and vemurafenib exhibit activity against BRAF V600E, V600K, V600R, and V600D mutations [ 61 ]. While BRAF-inhibitor monotherapy is effective initially, most patients develop resistance via reactivation of the MAPK pathway. It was theorized that the addition of MEK inhibition to BRAF inhibition could overcome the development of acquired resistance to BRAF inhibitors by blocking ERK signaling. BRAF inhibitors in combination with MEK inhibitors resulted in increased tolerability and efficacy, leading to several combination therapies being improved (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib) in BRAF V600E-mutant melanoma [ 64 , 65 , 66 ].

In metastatic NSCLC, dabrafenib plus trametinib was approved as a first-line treatment for patients with BRAF V600E-mutant metastatic NSCLC based on a phase II study showing a median PFS of 10.2 months and OS of 18.2 months in previously treated patients and a median PFS of 10.8 months and OS of 17.3 months in treatment-naïve patients [ 67 ]. Recently, encorafenib plus binimetinib was also approved for BRAF V600E-mutant NSCLC based on the phase II PHAROS trial demonstrating an ORR of 75% in treatment-naïve patients and 46% in previously treated patients with metastatic NSCLC harboring a BRAF V600E mutation [ 68 ]. Vemurafenib has also shown significant efficacy in this setting in combination with cobimetinib as seen in the phase 2 basket study TAPUR [ 69 , 70 ], which reported an ORR of 42% and PFS 7.3 months, and the EURAF [ 71 ] trial, which reported an ORR of 53% and a median PFS of 5 months. The mechanisms of acquired resistance to BRAF inhibitors alone or in combination with MEK inhibitors are poorly understood but are thought to occur through bypassing or reactivation of the MAPK pathway or a parallel pathway such as the PI3K/AKT pathway [ 72 ].

3.4. Novel Strategies to Target BRAF/MEK

Pan-RAF inhibitors : Pan-RAF inhibitors, or type II inhibitors, stabilize the α C-helix of RAF proteins into the active “in” position and DFG motif into the “out” position [ 73 , 74 ]. They may overcome resistance mechanisms seen with single RAF inhibitors by preventing compensatory activation of other RAF isoforms. Notably, pan-RAF inhibitors may impose greater risk of side effects and toxicities given their broad pathway inhibition. Sorafenib, a multitargeted tyrosine kinase inhibitor (TKI), is the only first-generation type II RAF inhibitor approved for clinical use and is indicated for the treatment of advanced renal cell carcinoma, unresectable hepatocellular carcinoma, and metastatic differentiated thyroid carcinoma. Multiple trials over the years have been conducted to assess the efficacy of sorafenib in the treatment of patients with advanced NSCLC; however, the results across trials reveal inconsistent and questionable benefit in DCR, PFS, and OS [ 75 , 76 , 77 ]. Several other pan-RAF inhibitors, including belvarafenib [ 78 ], naporafenib [ 79 ] (LXH254), exarafenib [ 80 ], and LY3009120 [ 81 ] are being investigated in early phase trials to better define their efficacy and safety across various solid tumor types.

Novel mutation-specific BRAF inhibitors: Next-generation BRAF inhibitors target dimerization, which plays a significant role in the activation of wild-type and mutant BRAF and plays a role in the acquired resistance to BRAF inhibitors. Data from preclinical and clinical studies suggest that BRAF non-V600E mutations could be targeted more effectively with these inhibitors. ABM-1310, a water-soluble, cell-permeable novel small molecule BRAF inhibitor with high blood–brain barrier penetration, is currently being investigated in a phase I multi-center study for the treatment of BRAF V600-mutated solid tumors in the United States ( NCT05501912 ) and in China ( NCT04190628 ) [ 82 ]. Other ongoing drug development strategies include BDTX-4933 as monotherapy in advanced BRAF or KRAS non-G12C-mutant NSCLC ( NCT05786924 ), PF-07799933 as monotherapy or in combination with binimetinib or cetuximab in BRAF-altered advanced solid tumors ( NCT05355701 ), and the combination of vemurafenib plus the MEK1/2 inhibitor tunlametinib (H-085) in BRAF -altered advanced solid tumors ( NCT03781219 ) [ 83 , 84 ]. Tovorafenib (TAK-580) is being studied in monotherapy or in combination with pimasertib ( NCT01425008 , NCT04985604 ) in recurrent, progressive, or refractory solid tumors with mutations in the MAPK pathway [ 85 ]. HLX208 is being studied as monotherapy in a phase II study of patients with BRAF V600-mutant advanced NSCLC in China ( NCT05065398 ).

MEK inhibitors : MEK inhibition leads to the loss of negative feedback and promotes upstream RAS and RTK activation, subsequently restricting the efficacy of MEK inhibitor monotherapy and inducing treatment resistance. It has also been theorized that MEK1/2 inhibition may modulate the KRAS -mutant NSCLC tumor immune microenvironment via altered chemokine secretion and increased T-cell recruitment [ 86 ]. In addition to trametinib, binimetinib, and cobimetinib which have demonstrated enhanced anti-tumor activity and improved response rates in combination with their respective BRAF inhibitors in patients with metastatic BRAF V600E-mutant NSCLC, MEK inhibitors are currently being explored in combination strategies with other targeted or immunotherapeutic agents in NSCLC. For example, the addition of MEK to KRAS G12C inhibition, as seen with the combination of trametinib and sotorasib, has exhibited anti-tumor efficacy and an acceptable safety profile in advanced KRAS G12C-mutated solid tumors [ 87 ]. Specifically in the NSCLC cohort, treatment-naïve patients achieved a DCR of 86.7% (13/15), and patients treated with a prior KRAS G12C inhibitor achieved a DCR of 66.7% (2/3). The most common TRAEs across all patients included diarrhea, rash, nausea, and vomiting, which were predominantly grade 1 or 2. Discontinuation of sotorasib and/or trametinib due to a TRAE occurred in 24.4% of patients.

RAF/MEK clamps are small molecules that prevent the phosphorylation and subsequent activation of MEK by RAF kinases. Avutometinib (VS-6766) is a RAF/MEK clamp that has shown strong anti-tumor potency across tumor cell lines carrying various MAPK pathway alterations in preclinical studies. In KRAS -mutant NSCLC cell lines, avutometinib also demonstrated synergistic activity in reducing tumor cell viability when combined with other agents, including sotorasib, adagrasib, the focal adhesion kinase inhibitor defactinib, and the mTOR inhibitor everolimus. Although limited clinical activity was ultimately seen with its combination with defactinib in metastatic KRAS G12V NSCLC in the phase II RAMP202 trial [ 88 ], efforts to evaluate other avutometinib combinations in KRAS -mutant NSCLC are ongoing ( NCT05074810 , NCT05375994 , NCT02407509 ). Preliminary data from the phase I/II RAMP203 trial demonstrated an ORR of 25% from the combination of avutometinib and sotorasib in KRAS G12C NSCLC ( NCT05074810 ) [ 89 ]. Most TRAEs observed with this regimen were grades 1 and 2; the most common TRAEs of any grade included nausea, diarrhea, fatigue, and pruritus. A phase I trial studying the combination of avutometinib and everolimus has also shown encouraging preliminary efficacy and safety results, with an ORR of 20%, DFS of 90%, and median PFS of 6.35 months in advanced KRAS -mutated NSCLC [ 90 ]. At the recommended phase II doses, the majority of patients developed rash, creatine kinase elevation, mouth ulcers, or diarrhea of grade 1 or 2 severity. The most common grade 3 and 4 TRAEs were rash (18%) and pruritis (7%). A comprehensive list of currently enrolling clinical trials with novel RAF/MEK inhibitors is listed in Table 2 .

Combination immunotherapy approaches : Studies have evaluated various combinations of anti-PD-1/PD-L1 therapies with BRAF and/or MEK inhibitors and have reported positive outcomes in solid tumors. In preclinical models, the use of MEK inhibitors reduced tumor cell proliferation, delayed tumor progression, and enhanced anti-tumor immunity of CD8 + T cells. Further activation of CD8 + T cells by synergistic targeting of PD-1/PD-L1 resulted in tumor regression and induced immunological memory [ 91 , 92 ]. The combination of cobimetinib plus atezolizumab across various solid tumors in a phase I/IB trial reported a median OS of 13.2 months and ORR of 18% in 28 patients with metastatic NSCLC [ 93 ]. Among all 150 patients enrolled in the study, the most common TRAE of any grade was diarrhea (67%), followed by rash (48%) and fatigue (40%). One patient died of sepsis, which was deemed to be related to treatment with atezolizumab. An active phase I trial is also investigating the combination of binimetinib and pembrolizumab in metastatic KRAS -mutant NSCLC [ 94 ]. A phase IB/II trial studying the combination of HLX208 with the anti-PD-1 antibody serplulimab (HLX10) in patients with BRAF V600E-mutant advanced solid tumors or NSCLC with PD-L1 TPS > 1% is also underway ( NCT05641493 ). Another study is evaluating the combination of pembrolizumab with binimetinib in patients with metastatic or advanced NSCLC with PD-L1 > 50%, and initial results reported 36% of patients with partial response ( NCT03991819 ) [ 95 ]. The most common toxicities were rash (82%), diarrhea (36%), and pruritis (36%). Some trials have investigated efficacy and safety of triple therapy combinations (BRAF/MEK inhibition in combination with anti-PD-1/PD-L1) in BRAF -mutant melanoma but have in general shown high rates of TRAEs [ 96 , 97 ].

4. HER3

4.1. Molecular Pathway

Unlike other family members, HER3 contains negligible kinase activity [ 98 ]. It possesses only a single ligand called heregulin or neuregulin. When a ligand binds to the extracellular region of HER3, this receptor interaction results in conformational changes facilitating dimerization, which subsequently activates downstream signaling pathways [ 99 ]. HER3 acts as a heterodimeric partner for other members of the EGFR family, namely EGFR and HER2 [ 100 ]. For example, HER3 becomes activated by dimerizing with mutated EGFR and mediates the PI3K/AKT pathway, which promotes cell survival, growth, and proliferation. The dimerization is often intensified during EGFR TKI treatment, which leads to therapy resistance and emphasizes the complexity of the EGFR/HER3 axis [ 101 ]. The most potent signaling occurs from the heterodimerization of HER3 with HER2, which functions to drive HER2-mediated PI3K downstream signaling. Increasing evidence supports HER3 to be an attractive target and inhibition of HER3 is now thought to be required to overcome therapy resistance and improve efficacy and outcomes in patients with metastatic NSCLC [ 102 ].

4.2. Clinical Characteristics

HER3, also known as ERBB3, is a member of the human epidermal receptor (HER) family of receptor tyrosine kinases, which also includes EGFR (ERBB1), HER2 (ERBB2), and HER4 (ERBB4) [ 103 ]. HER3 overexpression is observed in approximately 40% of NSCLC cases and is correlated with poor clinical outcomes [ 104 , 105 ]. HER3 activation leads to downstream PI3K/AKT pathway signaling, promoting cell survival and imparting resistance to EGFR-targeted therapies, which remains a cornerstone of treatment for EGFR-mutated NSCLC [ 106 ]. Activating mutations in HER3 have been identified and examined as direct therapeutic targets in NSCLC. While both EGFR and HER2 are excellent targets and a number of targeted therapies have been successfully transformed to the clinic for patients with EGFR - or HER2 -mutated NSCLC, there is no Food and Drug Administration (FDA)-approved HER3-targeted therapy for cancer treatment.

4.3. Treatments

Treatment strategies are focused on the prevention of HER3 activation by inhibiting the kinase activity of its dimerization partner, impeding its dimerization with other ERBB members, or directly targeting the HER3 extracellular domain. The HER2-HER3 heterodimer is a potent oncogenic unit with remarkably high enzymatic potency and the ability to interact with multiple copies of downstream effectors [ 107 ]. As such, attention has been placed on targeting HER2-HER3 using TKIs against EGFR or HER2 such as lapatinib or anti-HER2 monoclonal antibodies like trastuzumab and pertuzumab. TKIs compete with ATP binding and prevent phosphorylation of the HER3 C-terminal tail. Trastuzumab and pertuzumab bind to the HER2 extracellular domain and prevent ligand-dependent dimerization between HER2 and HER3 [ 108 ]. However, many studies have implicated that these inhibitory effects are merely transient, and HER3 signaling resumes despite continued drug exposure and effective suppression of EGFR and HER2 due to AKT-mediated negative feedback signaling [ 109 ].

Given the upregulation of HER3 in resistance to EGFR- or HER2-targeted therapy, the use of HER3-targeted monotherapy or combination strategies has been suggested to overcome acquired resistance mechanisms and augment tumor inhibition [ 108 , 110 ]. Despite its lack of intrinsic kinase activity, HER3 can be targeted via direct blockade of its extracellular domain via antibodies. Patritumab was the first fully humanized anti-HER3 antibody and has shown promising results in early-phase clinical trials, including its ability to overcome heregulin-dependent resistance to EGFR TKIs in NSCLC [ 111 ]. Patritumab deruxtecan, an antibody–drug conjugate (ADC) which contains a topoisomerase I inhibitor payload, was investigated in the phase II HERTHENA-Lung01 study in patients with advanced EGFR-mutated NSCLC who had progressed following EGFR TKI and platinum-based chemotherapy [ 112 ]. Treatment with patritumab deruxtecan demonstrated clinical efficacy and durable intracranial responses, with an ORR of 29.8% (95% CI, 23.9–36.2), median PFS of 5.5 months, median OS of 11.9 months, and intracranial ORR of 33.3% (95% CI, 17.3–52.8). TRAEs of grade 3 or 4 occurred in 64.9% and 28.9% of patients, respectively. The most frequent grade ≥ 3 TRAEs were hematologic toxicities, including thrombocytopenia (20.9%) and neutropenia (19.1%). Treatment-related discontinuation due to adverse events was low (7.1%). A phase III randomized trial evaluating patritumab deruxtecan versus platinum-based chemotherapy after failure of EGFR TKI therapy is ongoing in metastatic or locally advanced EGFR-mutant NSCLC in the HERTHENA-Lung02 trial ( NCT 05338970 ).

Lumretuzumab, another HER3-targeting antibody, was studied in a phase IB/II study in combination with carboplatin and paclitaxel as a first-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer. In the three out of 12 patients who achieved a partial response, a higher expression of tumoral heregulin mRNA levels was reported [ 113 ]. All patients experienced at least one adverse event, with the most frequent TRAEs being diarrhea (75%), asthenia (66.7%), and neurotoxicity (41.7%). DB-1310 is another HER3 ADC comprising a novel humanized anti-HER3 immunoglobulin G1 (IgG1) monoclonal antibody, covalently linked to a proprietary DNA topoisomerase I inhibitor payload. DB-1310 demonstrated more potent anti-tumor activity than patritumab deruxtecan in vitro and in vivo [ 114 ]. Preclinical data support dual targeting of EGFR and HER3 to overcome acquired resistance to EGFR inhibition. An ongoing phase I trial is exploring patritumab in combination with osimertinib in advanced EGFR-mutated NSCLC [ 115 ]. Izalontamab (SI-B001) is a bispecific antibody which binds both EGFR and HER3 to inhibit the formation of EGFR × EGFR homodimers and EGFR × HER3 heterodimers and subsequently prevent the activation of downstream pathways. In a phase II study, SI-B001 demonstrated anti-tumor activity with manageable toxicity when combined with chemotherapy in locally advanced or metastatic EGFR/ALK wild-type NSCLC in the second-line setting [ 116 ]. Table 3 lists ongoing clinical trials evaluating HER3 -targeted agents.

5. Nectin-4

5.1. Molecular Pathway

Nectin-4 is a cell adhesion molecule that belongs to the Nectin family, which also includes Nectin-1, -2, and -3 [ 117 ]. It comprises three parts: an extracellular region, a transmembrane region, and a cytoplasmic tail. The precise mechanism by which Nectin-4 participates in cancer progression is not clear. However, several studies have implicated the translocation of its intracellular domain into the nucleus via physical interaction with the nuclear transport receptor importin-a2, thus activating DNA repair and enhancing cell growth. In addition, the extracellular domain of Nectin-4 can increase angiogenesis via modulation of angiogenic markers. Other studies have confirmed its role in the adhesion, migration, and proliferation of tumor cells [ 118 ].

5.2. Clinical Characteristics

Nectin-4 plays a significant role in cancer development, mediating several functions including cell proliferation, differentiation, migration, and invasion [ 119 ]. Nectin-4 is highly expressed in various solid tumors and has emerged as a potential new biomarker and therapeutic target [ 120 ]. Nectin-4 is overexpressed in over 60% of NSCLC cases [ 121 ].

5.3. Treatments

Because of its high expression across multiple tumor types, Nectin-4 has emerged as an attractive target for the treatment of various cancers including NSCLC. Enfortumab vedotin, an ADC comprising a Nectin-4-directed antibody and microtubule inhibitor conjugate, first received approval for the treatment of patients with advanced or metastatic urothelial cancer. Its use is now being explored in other previously treated advanced solid tumors including NSCLC ( NCT04225117 ) [ 122 ]. In a cohort of 43 patients with heavily pretreated NSCLC of non-squamous histology from the phase II EV-202 trial, enfortumab vedotin demonstrated an ORR of 14% and manageable safety profile with primarily grade 1 or 2 TRAEs (70%). The most common TRAEs were maculopapular rash (37%), peripheral neuropathy (37%), pruritus (35%), and alopecia (33%). Unfortunately, enrollment for those with squamous histology closed as only one of the 20 patients (ORR 4.3%) in the squamous cohort had achieved a response. BT8009 is a bicycle toxin conjugate consisting of a Nectin-4-targeting bicyclic peptide and cytotoxic payload that has demonstrated potent anti-tumor activity in rodent models [ 123 ]. The efficacy and safety of BT8009 in patients with Nectin-4-expressing advanced solid tumors will be studied in the Duravelo-1 study ( NCT04561362 ). Table 4 lists currently-recruiting clinical trials with novel agents targeting Nectin-4, in addition to other targets including folate receptor alpha, ITGB6, and PRMT5.

6. Folate Receptor Alpha

6.1. Molecular Pathway

Folate receptor alpha (FRα) binds strongly to oxidized folate and, via potocytosis, transports it to the cytoplasm. Following folate uptake and internalization, FRα can translocate to the nucleus, where it can act as a transcription factor and directly regulate the expression of key development genes in cancer cells. This sets off a series of intracellular signaling cascades including the ERK and JAK/STAT3 pathway via phosphorylation and activates regulatory mechanisms involved in cell growth and proliferation. Furthermore, folate uptake can assist cancer cell proliferation and invasion by downregulating the expression of adhesion molecules such as E-cadherin, thus promoting cellular motility and metastasis.

6.2. Clinical Characteristics

FRα is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein encoded by the gene FOLR1 . It binds with high affinity to folic acid and its derivatives and mediates several cellular processes including cellular division, proliferation, and growth. High expression of FRα has been observed in several tumor types, including ovarian, endometrial, lung, and triple-negative breast cancer [ 124 , 125 , 126 , 127 ]. FRα was found to have a high discriminatory capacity based on the histologic subtype of lung cancer, with one study demonstrating an FRα positivity rate of 74% in adenocarcinomas vs. 13% in squamous cell carcinomas of the lung. Furthermore, high FRα expression was associated with improved overall survival in patients with LUAD who underwent surgical resection [ 128 ].

6.3. Treatments

Given its overexpression in NSCLC, FRα serves as a potential novel target for therapies using humanized monoclonal antibodies. Farletuzumab Ecteribulin (MORAb-202) is an ADC composed of a monoclonal antibody directed against FRα conjugated to the microtubule inhibitor eribulin. In a phase I study, Farletuzumab Ecteribulin was shown to have a DCR of 81.8% in patients with FRα-positive solid tumors ( NCT03386942 ) [ 129 ]. TRAEs occurred in 95% of the patients, the most common of which were leukopenia (45%) and neutropenia (45%). Additionally, 23% of patients were identified to have grade 1 or 2 interstitial lung disease assessed to be related to MORAb-202. A phase II study investigating its use in patients with previously treated metastatic LUAD is actively recruiting ( NCT05577715 ).

7. ITGB6

7.1. Molecular Pathway

Integrins are heterodimeric glycoprotein receptors that modulate intracellular signal transduction cascades in control of cell motility, survival, proliferation, and differentiation. They consist of alpha and beta subunits which span the cell membrane and have large extracellular domains, single transmembrane domains, and short intracellular tails. They mediate cell adhesion by binding to components of the extracellular matrix and transducing signals intracellularly. Activation of integrins results in conformational changes and triggers the formation of membrane extensions required for cell motility on ECM surfaces, migration of cells into sheets of other cells, and cell survival in foreign microenvironments [ 130 , 131 ].

ITGB6 encodes the β6 subunit of integrin αvβ6, which works via its extracellular domain to convert latent transforming growth factor beta (TGF β ) into its active form, which exerts growth inhibitory and transcriptional responses through the SMAD signaling pathway [ 132 ]. Deregulation of integrin αvβ6 and hereby TGF β signaling has been implicated in tumorigenesis and progression [ 133 , 134 , 135 ]. Moreover, TGF β is well known to promote T-cell suppression within tumor microenvironments and mediate resistance to immunotherapies [ 136 , 137 ].

7.2. Clinical Characteristics

The integrin- β superfamily (ITGBs) is comprised of eight members, ITGB1–8 . ITGB6 is overexpressed in numerous solid tumors of epithelial origin, including NSCLC, colorectal, gastric, and cervical cancers [ 138 , 139 , 140 ]. In these carcinomas, its expression has been correlated with increased disease progression and poor prognosis [ 138 , 141 , 142 ]. ITGB6 is expressed at low levels in healthy adult lung epithelial tissue but is rapidly upregulated in areas of subclinical or clinical inflammation, suggesting its role in cell spreading, migration, and growth during morphogenetic events, tissue repair, and neoplasia [ 143 ].

7.3. Treatments

As a target for inducing an immune-mediated anti-tumor response, integrin αvβ6 has considerable therapeutic implications in NSCLC [ 138 ]. Sigvotatug Vedotin (SGN-B6A) is a novel ADC comprising a monoclonal antibody directed to integrin αvβ6 to deliver the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells. SGN-B6A induces immunogenic cell death, thus promoting the activation and recruitment of immune cells to the tumor environment [ 144 ]. Combinations with immune checkpoint inhibition may also represent a promising approach to harness the potential of integrin αvβ6 inhibition. An ongoing phase I trial is investigating the use of SGN-B6A alone and in combination with pembrolizumab, with or without chemotherapy, in patients with advanced solid tumors that are relapsed or refractory or intolerant to standard-of-care treatments ( NCT04389632 ) [ 145 ]. A total of 113 patients with NSCLC treated with SGN-B6A monotherapy were included in the interim analysis, with a median of three prior lines of therapy. Preliminary efficacy results within the NSCLC cohort showed an ORR of 19.5% (95% CI, 12.6–28.0%), median DOR of 8.4 months (95% CI, 1.4–22.1), and median PFS of 3.5 months (95% CI, 2.7–4.9). Grade 3 or 4 TRAEs occurred in 46% of the patients, with the most common grade ≥ 3 TRAEs being dyspnea (9.7%), fatigue (7.1%), and neutropenia (5.3%). The promising single-agent activity of SGN-B6A seen has since prompted the initiation of the phase III SGNB6A-002 study, which will compare SGN-B6A to docetaxel in patients with previously treated advanced or metastatic non-squamous NSCLC ( NCT06012435 ).

8. PRMT5

8.1. Molecular Pathway

The protein arginine methyltransferase (PRMT) family of enzymes is responsible for the methylation of arginine residues on histone proteins, a post-translational modification process that plays an important regulatory role in maintaining cellular homeostasis [ 146 ]. PRMT5 plays a complex role in oncogenesis, as its methylation of proteins is implicated in both tumor promotion and suppression across various tumor types [ 147 ]. In lung tumors, the PRMT5-driven arginine methylation of the N-terminal tails of histones H3 and H4 can modulate chromatin structure to induce transcriptional silencing of regulatory and tumor suppressor genes [ 148 ]. As seen in patient-derived xenograft models of LUAD, PRMT5 represses miR-99 family transcription via dimethylation of histone H4R3 [ 149 , 150 ]. This in turn increases FGFR3 expression, which activates its downstream molecules ERK1/2 and AKT to promote the growth, migration, and invasion of lung cancer cells [ 148 , 151 ].

Additionally, emerging evidence has shown the loss of tumor suppressor gene CDKN2A to be commonly accompanied by co-deletion of the proximal gene, methylthioadenosine phosphorylase (MTAP) , which encodes a major enzyme in the methionine salvage pathway [ 152 ]. MTAP deletion causes the accumulation of cellular metabolite methylthioadenosine (MTA), which binds to and partially inhibits PRMT5. As such, cancers harboring MTAP deletion are more sensitive to additional PRMT5 inhibition than normal cells [ 153 ].

8.2. Clinical Characteristics

The PRMT family is comprised of at least nine known members, PRMTs 1–9. PRMT5 is the primary enzyme responsible for the mono- and dimethylation of arginine and functions as a key player in a wide range of cellular and transcriptional processes including gene transcription, splicing, signal transduction, and cell cycle regulation [ 154 ]. PRMT5 overexpression has been implicated in tumor development and the progression of various cancers, including breast, hepatocellular, brain, and lung [ 155 , 156 , 157 , 158 , 159 ]. In NSCLC, growing evidence has also designated PRMT5 as a marker of poor clinical outcomes [ 155 , 160 , 161 ].

8.3. Treatments

PRMT5 has emerged as a synthetically lethal drug target for the treatment of MTAP -deleted cancers. The first generation of PRMT5 inhibitors that were developed did not demonstrate sufficient selectivity for MTAP-deleted cancer cell lines and resulted in intolerability from dose-limiting myelosuppression [ 162 , 163 , 164 ]. Next-generation PRMT5 inhibitors such as MRTX1719, TNG908, and TNG462 were subsequently designed to fully inhibit PRMT5 activity in MTAP-deficient cancer cells while sparing normal cells [ 165 , 166 ]. Following its encouraging preclinical data, MRTX1719 is now being explored in a phase I/II study in patients with advanced solid tumors with MTAP deletion ( NCT05245500 ). Early results have confirmed ORRs in six of 18 patients (ORR 33.3%), including one patient with NSCLC harboring EGFR mutation and both EGFR and MET gene amplification who progressed after treatment with osimertinib and achieved a partial response after five cycles of MRTX1719 [ 165 ]. Similar phase I/II trials are currently investigating TNG908 and TNG462 for the treatment of advanced MTAP-deleted solid tumors ( NCT05275478 , NCT05732831 ) [ 166 ]. AMG193 is another second-generation PRMT5 inhibitor that selectively targets the MTA-bound state of PRMT5 that is enriched in MTAP-null tumors. It has demonstrated potent anti-tumor activity in MTAP-null cancer cell lines and tumor xenograft models and will be further studied in a first-in-human phase I/II trial in patients with advanced solid tumors with confirmed MTAP deletion ( NCT05094336 ) [ 167 ].

9. Conclusions

Targeted therapy has successfully revolutionized the treatment paradigm of oncogene-driven early-stage and advanced NSCLC. Apart from the targets we have reviewed here, several others have been suggested including NSD3, ATR, FGFR, NRF2, AXL, and others [ 168 ]. Further, the evaluation of novel combinatorial strategies including targeted and immunologic treatment approaches is ongoing and will inform future treatment strategies. Treatment resistance and failure eventually occurs and remains the primary challenge for NSCLC-targeted therapeutics. The etiology of treatment resistance is complex and multifactorial and involves the complexity of intra- and inter-tumoral heterogeneity, mutations which develop from selective pressure of targeted therapy, and cancer genome evolution [ 169 ]. We expect the field of targeted therapy in NSCLC to continue to evolve, with a goal of optimizing personalized targeted approaches to further outcomes and survival in patients with metastatic NSCLC.

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Author Contributions

Conception and design: L.L. and K.S. Administrative support: N/A. Provisions of study materials or patients: N/A. Collection and assembly of data: N/A. Data analysis and interpretation: all authors. Manuscript writing: all authors. Final approval of the manuscript: all authors. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

L.L. and J.S. have no conflicts of interest to disclose. K.S.: Research funding to institution: Genentech; Black Diamond; Lilly; Harpoon Therapeutics; Merck. K.R.: Consultant with honoraria to self: Amgen; AstraZeneca; Blueprint; Daiichi Sankyo; Genentech; GlaxoSmithKline; Janssen; Lilly; Mirati; Novartis; Novocure. Research funding to institution: Genentech; Blueprint; Daiichi Sankyo; Elevation Oncology; Janssen.

References

1. Ettinger D.S. Wood D.E. Aisner D.L. Akerley W. Bauman J.R. Bharat A. Bruno D.S. Chang J.Y. Chirieac L.R. D’Amico T.A. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology J. Natl. Compr. Canc. Netw. 2022 20 497 530 10.6004/jnccn.2022.0025 35545176

2. Majeed U. Manochakian R. Zhao Y. Lou Y. Targeted therapy in advanced non-small cell lung cancer: Current advances and future trends J. Hematol. Oncol. 2021 14 108 10.1186/s13045-021-01121-2 34238332 PMC8264982

3. Olmedo M.E. Cervera R. Cabezon-Gutierrez L. Lage Y. Corral de la Fuente E. Gómez Rueda A. Mielgo-Rubio X. Trujillo J.C. Couñago F. New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2 World J. Clin. Oncol. 2022 13 276 286 10.5306/wjco.v13.i4.276 35582653 PMC9052069

4. Hong D.S. Fakih M.G. Strickler J.H. Desai J. Durm G.A. Shapiro G.I. Falchook G.S. Price T.J. Sacher A. Denlinger C.S. KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors N. Engl. J. Med. 2020 383 1207 1217 10.1056/NEJMoa1917239 32955176 PMC7571518

5. Hong D.S. DuBois S.G. Kummar S. Farago A.F. Albert C.M. Rohrberg K.S. van Tilburg C.M. Nagasubramanian R. Berlin J.D. Federman N. Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials Lancet Oncol. 2020 21 531 540 10.1016/S1470-2045(19)30856-3 32105622 PMC7497841

6. Yu Y. Yang Y. Li H. Fan Y. Targeting HER2 alterations in non-small cell lung cancer: Therapeutic breakthrough and challenges Cancer Treat. Rev. 2023 114 102520 10.1016/j.ctrv.2023.102520 36738637

7. Rebuzzi S.E. Zullo L. Rossi G. Grassi M. Murianni V. Tagliamento M. Prelaj A. Coco S. Longo L. Dal Bello M.G. Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer Int. J. Mol. Sci. 2021 22 2625 10.3390/ijms22052625 33807876 PMC7961376

8. Cox A.D. Der C.J. Philips M.R. Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery? Clin. Cancer Res. 2015 21 1819 1827 10.1158/1078-0432.CCR-14-3214 25878363 PMC4400837

9. Takashima A. Faller D.V. Targeting the RAS oncogene Expert Opin. Ther. Targets 2013 17 507 531 10.1517/14728222.2013.764990 23360111 PMC3804031

10. Mitin N. Rossman K.L. Der C.J. Signaling interplay in Ras superfamily function Curr. Biol. 2005 15 R563 R574 10.1016/j.cub.2005.07.010 16051167

11. Román M. Baraibar I. López I. Nadal E. Rolfo C. Vicent S. Gil-Bazo I. KRAS oncogene in non-small cell lung cancer: Clinical perspectives on the treatment of an old target Mol. Cancer 2018 17 33 10.1186/s12943-018-0789-x 29455666 PMC5817724

12. Reita D. Pabst L. Pencreach E. Guérin E. Dano L. Rimelen V. Voegeli A.C. Vallat L. Mascaux C. Beau-Faller M. Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance Cancers 2022 14 1321 10.3390/cancers14051321 35267628 PMC8909472

13. Liao W. Overman M.J. Boutin A.T. Shang X. Zhao D. Dey P. Li J. Wang G. Lan Z. Tang M. KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer Cancer Cell 2019 35 559 572.e557 10.1016/j.ccell.2019.02.008 30905761 PMC6467776

14. Cox A.D. Fesik S.W. Kimmelman A.C. Luo J. Der C.J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov. 2014 13 828 851 10.1038/nrd4389 25323927 PMC4355017

15. Singhal A. Li B.T. O’Reilly E.M. Targeting KRAS in cancer Nat. Med. 2024 30 969 983 10.1038/s41591-024-02903-0 38637634 PMC11845254

16. Judd J. Abdel Karim N. Khan H. Naqash A.R. Baca Y. Xiu J. VanderWalde A.M. Mamdani H. Raez L.E. Nagasaka M. Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer Mol. Cancer Ther. 2021 20 2577 2584 10.1158/1535-7163.MCT-21-0201 34518295 PMC9662933

17. Nassar A. Adib E. Kwiatkowski D. Distribution of KRAS G12C Somatic Mutations across Race, Sex, and Cancer Type N. Engl. J. Med. 2021 384 185 187 10.1056/NEJMc2030638 33497555

18. Salgia R. Pharaon R. Mambetsariev I. Nam A. Sattler M. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC) Cell Rep. Med. 2021 2 100186 10.1016/j.xcrm.2020.100186 33521700 PMC7817862

19. Ostrem J.M. Peters U. Sos M.L. Wells J.A. Shokat K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions Nature 2013 503 548 551 10.1038/nature12796 24256730 PMC4274051

20. Hong D. Yaeger R. Kuboki Y. Masuishi T. Barve M. Falchook S. Govindan R. A phase 1b study of sotorasib, a specific and irreversible KRAS G12C inhibitor, in combination with other anticancer therapies in advanced colorectal cancer (CRC) and other solid tumors (CodeBreaK 101) J. Clin. Oncol. 2022 40 TPS214 10.1200/JCO.2022.40.4_suppl.TPS214

21. de Langen A.J. Johnson M.L. Mazieres J. Dingemans A.C. Mountzios G. Pless M. Wolf J. Schuler M. Lena H. Skoulidis F. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS Lancet 2023 401 733 746 10.1016/S0140-6736(23)00221-0 36764316

22. Ou S.I. Jänne P.A. Leal T.A. Rybkin I.I. Sabari J.K. Barve M.A. Bazhenova L. Johnson M.L. Velastegui K.L. Cilliers C. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients with Advanced KRAS G12C Solid Tumors (KRYSTAL-1) J. Clin. Oncol. 2022 40 2530 2538 10.1200/JCO.21.02752 35167329 PMC9362872

23. Mok T. Yao W. Duruisseaux M. Doucet L. Martinez A. Gregorc V. Juan-Vidal O. Lu S. De Bondt C. De Marinis F. KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation J. Clin. Oncol. 2024 42 LBA8509 10.1200/JCO.2024.42.17_suppl.LBA8509

24. Wang P. Zheng Q. Kang D. Sun X. Zhu S. Wang Y. Long W. Lin Y. Investigation of KRAS G12C inhibitor JAB-21822 as a single agent and in combination with SHP2 inhibitor JAB-3312 in preclinical cancer models Ann. Oncol. 2022 33 S1441 10.1016/j.annonc.2022.10.040

25. Shi Y. Fang J. Xing L. Yao Y. Zhang J. Liu L. Wang Y. Hu C. Xiong J. Liu Z. A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation J. Clin. Oncol. 2024 42 468214 10.1200/JCO.2024.42.36_suppl.468214

26. Brazel D. Nagasaka M. Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC Target. Oncol. 2024 19 297 301 10.1007/s11523-024-01055-y 38739329 PMC11111488

27. Sacher A. LoRusso P. Patel M.R. Miller W.H. Garralda E. Forster M.D. Santoro A. Falcon A. Kim T.W. Paz-Ares L. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation N. Engl. J. Med. 2023 389 710 721 10.1056/NEJMoa2303810 37611121

28. Peng S. Si C. Zhang Y. Van Horn R. Lin X. Gong X. Huber L. Donoho G. Curtis C. Strelow J. Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor Cancer Res. 2021 81 1259 10.1158/1538-7445.AM2021-1259

29. Murciano-Goroff Y. Heist R. Kuboki Y. Koyama T. Ammakkanavar N. Hollebecque A. Patnaik A. Shimizu T. Spira A. CT028: A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors Cancer Res. 2023 83 CT028 10.1158/1538-7445.AM2023-CT028

30. Negrao M. Arbour K. Burns T. Cappuzzo F. Dingemans A. Girard N. Gronberg B. Hochmair M. Leal T. Lindsay C.R. SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in combination with pembrolizumab with or without chemotherapy for 1L treatment in KRAS G12C-mutant advanced NSCLC J. Clin. Oncol. 2024 42 TPS8649 10.1200/JCO.2024.42.16_suppl.TPS8649

31. Weiss A. Lorthiois E. Barys L. Beyer K.S. Bomio-Confaglia C. Burks H. Chen X. Cui X. de Kanter R. Dharmarajan L. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C Cancer Discov. 2022 12 1500 1517 10.1158/2159-8290.CD-22-0158 35404998 PMC9394399

32. Cassier P. Dooms C. Gazzah A. Felip E. Steeghs N. Rohrberg K. De Braud F. Solomon B. Schuler M. KontRASt-01 update: Safety and efficacy of JDQ443 in KRAS G12C -mutated solid tumors including non-small cell lung cancer (NSCLC) J. Clin. Oncol. 2023 41 9007 10.1200/JCO.2023.41.16_suppl.9007

33. Cappuzzo F. Castro G. Kang J. Wu Y. Brustugun O. Cheema P. Owonikoko T. Longin A. Boran A. KontRASt-02: A phase III trial investigating the efficacy and safety of the KRASG12C inhibitor JDQ443 vs docetaxel in patients with previously treated, locally advanced or metastatic, KRAS G12C-mutated NSCLC J. Clin. Oncol. 2023 41 TPS9144 10.1200/JCO.2023.41.16_suppl.TPS9144

34. Shi Z. Weng J. Niu H. Yang H. Liu R. Weng Y. Zhu Q. Zhang Y. Tao L. Wang Z. D-1553: A novel KRAS G12C inhibitor with potent and selective cellular and in vivo antitumor activity Cancer Sci. 2023 114 2951 2960 10.1111/cas.15829 37158138 PMC10323112

35. Li Z. Song Z. Zhao Y. Wang P. Jiang L. Gong Y. Zhou J. Jian H. Dong X. Zhuang W. D-1553 (Garsorasib), a Potent and Selective Inhibitor of KRAS J. Thorac. Oncol. 2023 18 940 951 10.1016/j.jtho.2023.03.015 36948246

36. Mahadevan K.K. McAndrews K.M. LeBleu V.S. Yang S. Lyu H. Li B. Sockwell A.M. Kirtley M.L. Morse S.J. Moreno Diaz B.A. Oncogenic Kras G12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8+ T cells dependent manner bioRxiv 2023 10.1101/2023.02.15.528757

37. Zhou C. Song Z. Zhang Y. Huang D. Yang Z. Zhou M. LBA33 a first-in-human phase I study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation Ann. Oncol. 2023 34 S1273 10.1016/j.annonc.2023.10.025

38. Jiang L. Menard M. Weller C. Wang Z. Burnett L. Aronchik I. Steele S. Flagella M. Zhao R. Evans J. Abstract 526: RMC-9805, a first-in-class, mutant-selective, covalent and oral KRAS G12D (ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers Cancer Res. 2023 83 526 10.1158/1538-7445.AM2023-526

39. Farren M. Roman V. Gallion A. Allali-Hassani A. Sokolsky A. Kong W. Smith A. Wang H. Correa G. Abstract 5900: INCB161734: A Novel, Potent, and Orally Bioavailable KRAS G12D Selective Inhibitor Demonstrates Antitumor Activity in KRAS G12D Mutant Tumors Cancer Res. 2024 84 5900 10.1158/1538-7445.AM2024-5900

40. Zhao H.Y. Xin M. Zhang S.Q. Progress of small molecules for targeted protein degradation: PROTACs and other technologies Drug Dev. Res. 2023 84 337 394 10.1002/ddr.22026 36606428

41. Nagashima T. Yoshinari T. Nishizono Y. Tasaki M. Inamura K. Ishioka H. Suzuki A. Osaki F. Yamanaka Y. Hayakawa M. Abstract 5735: Novel KRAS G12D degrader ASP3082 demonstrates in vivo, dose-dependent KRAS degradation, KRAS pathway inhibition, and antitumor efficacy in multiple KRAS G12D-mutated cancer models Cancer Res. 2023 83 5735 10.1158/1538-7445.AM2023-5735

42. Tolcher A. Park W. Wang J. Spira A. Janne P. Lee H. Gill S. LoRusso P. Herzberg B. Trial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations J. Clin. Oncol. 2023 41 TPS764 10.1200/JCO.2023.41.4_suppl.TPS764

43. Gustafson W. Wildes D. Rice M. Lee B. Jiang J. Wang Z. Chang S. Flagella M. Mu Y. Direct targeting of RAS in pancreatic ductal adenocarcinoma with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RAS MULTI (ON) inhibitor J. Clin. Oncol. 2022 40 591 10.1200/JCO.2022.40.4_suppl.591

44. Arbour K. Punekar S. Garrido-Laguna I. Hong D. Wolpin B. Pelster M. Barve M. Starodub A. Sommerhalder D. Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) Ann. Oncol. 2023 34 S458 10.1016/j.annonc.2023.09.1838

45. Tolani B. Celli A. Yao Y. Tan Y.Z. Fetter R. Liem C.R. de Smith A.J. Vasanthakumar T. Bisignano P. Cotton A.D. Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice Nat. Biotechnol. 2022 40 1834 1844 10.1038/s41587-022-01386-z 35879364 PMC9750872

46. Zhang Y. Rominger D. Vo E. Silva J. Zhang Y. Lee G. Micozzi J. Reid B. McDonough B. Hospital A. Discovery and characterization of QTX3034, a potent, selective, and orally bioavailable allosteric KRAS inhibitor Cancer Res. 2023 83 LB320 10.1158/1538-7445.AM2023-LB320

47. Xu Z. Weaver D. Drakas R. Lou Y. The small molecule KRAS inhibitor, TEB-17231, blocks tumor progression and overcomes KRAS G12C inhibitor mediated resistance Cancer Res. 2023 83 2627 10.1158/1538-7445.AM2023-2627

48. Patnaik A. Pelster M. Hong D. Strickler J. Garrido-Laguna I. Aguirre A. Curran D. Woo T. Spira A. A phase 1 trial evaluating the safety, tolerability, PK, and preliminary efficacy of QTX3034, an oral G12D-preferring multi-KRAS inhibitor, in patients with solid tumors with KRAS G12D mutation J. Clin. Oncol. 2024 42 TPS3172 10.1200/JCO.2024.42.16_suppl.TPS3172

49. Monsen H. Norseth H. Remen N. Abrahamsen I. Lysén A. Schjesvold F. PB2118: TG01-STUDY: A Phase 1/2 Study with Tg01 Immunotherapy Vaccination in Patients with Confirmed Nras/Kras Mutation on Codon 12/13 and Multiple Myeloma or High-Risk Smoldering Myeloma HemaSphere 2023 7 e51467aa 10.1097/01.HS9.0000975244.51467.aa

50. Palmer D.H. Valle J.W. Ma Y.T. Faluyi O. Neoptolemos J.P. Jensen Gjertsen T. Iversen B. Amund Eriksen J. Møller A.S. Aksnes A.K. TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas (CT TG01-01): A single-arm, phase 1/2 trial Br. J. Cancer 2020 122 971 977 10.1038/s41416-020-0752-7 32063605 PMC7109101

51. Haldar S. Heumann T. Berg M. Ferguson A. Lim S. Wang H. Nauroth J. Lahertu D. Jaffee E. Azad N. A phase I study of a mutant KRAS-targeted long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer and MMR-proficient metastatic colorectal cancer J. Clin. Oncol. 2023 41 TPS814 10.1200/JCO.2023.41.4_suppl.TPS814

52. Seenappa L.M. Jakubowski A. Steinbuck M.P. Palmer E. Haqq C.M. Carter C. Fontenot J. Villinger F. McNeil L.K. DeMuth P.C. Amphiphile-CpG vaccination induces potent lymph node activation and COVID-19 immunity in mice and non-human primates NPJ Vaccines 2022 7 128 10.1038/s41541-022-00560-3 36307453 PMC9616425

53. Ma L. Hostetler A. Morgan D.M. Maiorino L. Sulkaj I. Whittaker C.A. Neeser A. Pires I.S. Yousefpour P. Gregory J. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity Cell 2023 186 3148 3165.e3120 10.1016/j.cell.2023.06.002 37413990 PMC10372881

54. O’Reilly E. Wainberg Z. Weekes C. Furqan M. Kasi P. Devoe C. Leal A. Chung V. Perry J. AMPLIFY-201, a first-in-human safety and efficacy trial of adjuvant ELI-002 2P immunotherapy for patients with high-relapse risk with KRAS G12D- or G12R-mutated pancreatic and colorectal cancer J. Clin. Oncol. 2023 41 2528 10.1200/JCO.2023.41.16_suppl.2528

55. Wang X. Wang W. Zou S. Xu Z. Cao D. Zhang S. Wei M. Zhan Q. Wen C. Li F. Combination therapy of KRAS G12V mRNA vaccine and pembrolizumab: Clinical benefit in patients with advanced solid tumors Cell Res. 2024 34 661 664 10.1038/s41422-024-00990-9 38914844 PMC11369195

56. Imbimbo M. Wetterwald L. Friedlaender A. Parikh K. Addeo A. Cellular Therapy in NSCLC: Between Myth and Reality Curr. Oncol. Rep. 2023 25 1161 1174 10.1007/s11912-023-01443-z 37646900 PMC10556121

57. Katiyar V. Chesney J. Kloecker G. Cellular Therapy for Lung Cancer: Focusing on Chimeric Antigen Receptor T (CAR T) Cells and Tumor-Infiltrating Lymphocyte (TIL) Therapy Cancers 2023 15 3733 10.3390/cancers15143733 37509394 PMC10377757

58. Domingo E. Niessen R.C. Oliveira C. Alhopuro P. Moutinho C. Espín E. Armengol M. Sijmons R.H. Kleibeuker J.H. Seruca R. BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes Oncogene 2005 24 3995 3998 10.1038/sj.onc.1208569 15782118

59. Davies H. Bignell G.R. Cox C. Stephens P. Edkins S. Clegg S. Teague J. Woffendin H. Garnett M.J. Bottomley W. Mutations of the BRAF gene in human cancer Nature 2002 417 949 954 10.1038/nature00766 12068308

60. Cardarella S. Ogino A. Nishino M. Butaney M. Shen J. Lydon C. Yeap B.Y. Sholl L.M. Johnson B.E. Jänne P.A. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer Clin. Cancer Res. 2013 19 4532 4540 10.1158/1078-0432.CCR-13-0657 23833300 PMC3762878

61. Planchard D. Sanborn R.E. Negrao M.V. Vaishnavi A. Smit E.F. BRAF V600E-mutant metastatic NSCLC: Disease overview and treatment landscape NPJ Precis. Oncol. 2024 8 90 10.1038/s41698-024-00552-7 38627602 PMC11021522

62. Marchetti A. Felicioni L. Malatesta S. Grazia Sciarrotta M. Guetti L. Chella A. Viola P. Pullara C. Mucilli F. Buttitta F. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations J. Clin. Oncol. 2011 29 3574 3579 10.1200/JCO.2011.35.9638 21825258

63. Negrao M.V. Skoulidis F. Montesion M. Schulze K. Bara I. Shen V. Xu H. Hu S. Sui D. Elamin Y.Y. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer J. Immunother. Cancer 2021 9 e002891 10.1136/jitc-2021-002891 34376553 PMC8356172

64. Long G.V. Stroyakovskiy D. Gogas H. Levchenko E. de Braud F. Larkin J. Garbe C. Jouary T. Hauschild A. Grob J.J. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma N. Engl. J. Med. 2014 371 1877 1888 10.1056/NEJMoa1406037 25265492

65. Ascierto P.A. Dréno B. Larkin J. Ribas A. Liszkay G. Maio M. Mandalà M. Demidov L. Stroyakovskiy D. Thomas L. 5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study Clin. Cancer Res. 2021 27 5225 5235 10.1158/1078-0432.CCR-21-0809 34158360 PMC9401485

66. Dummer R. Flaherty K.T. Robert C. Arance A. de Groot J.W.B. Garbe C. Gogas H.J. Gutzmer R. Krajsová I. Liszkay G. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients with BRAF V600–Mutant Melanoma J. Clin. Oncol. 2022 40 4178 4188 10.1200/JCO.21.02659 35862871 PMC9916040

67. Planchard D. Besse B. Groen H.J.M. Hashemi S.M.S. Mazieres J. Kim T.M. Quoix E. Souquet P.J. Barlesi F. Baik C. Phase 2 Study of Dabrafenib Plus Trametinib in Patients with BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis J. Thorac. Oncol. 2022 17 103 115 10.1016/j.jtho.2021.08.011 34455067

68. Riely G.J. Smit E.F. Ahn M.J. Felip E. Ramalingam S.S. Tsao A. Johnson M. Gelsomino F. Esper R. Nadal E. Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients with BRAFV600-Mutant Metastatic Non–Small-Cell Lung Cancer J. Clin. Oncol. 2023 41 3700 3711 10.1200/JCO.23.00774 37270692

69. Hyman D.M. Puzanov I. Subbiah V. Faris J.E. Chau I. Blay J.Y. Wolf J. Raje N.S. Diamond E.L. Hollebecque A. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations N. Engl. J. Med. 2015 373 726 736 10.1056/NEJMoa1502309 26287849 PMC4971773

70. Meric-Bernstam F. Rothe M. Mangat P.K. Garrett-Mayer E. Gutierrez R. Ahn E.R. Cannon T.L. Powell S. Krauss J.C. Reynolds C.M. Cobimetinib Plus Vemurafenib in Patients with Solid Tumors with BRAF Mutations: Results from the Targeted Agent and Profiling Utilization Registry Study JCO Precis. Oncol. 2023 7 e2300385 10.1200/PO.23.00385 38096472 PMC10735080

71. Gautschi O. Milia J. Cabarrou B. Bluthgen M.V. Besse B. Smit E.F. Wolf J. Peters S. Früh M. Koeberle D. Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort J. Thorac. Oncol. 2015 10 1451 1457 10.1097/JTO.0000000000000625 26200454

72. Ortiz-Cuaran S. Mezquita L. Swalduz A. Aldea M. Mazieres J. Leonce C. Jovelet C. Pradines A. Avrillon V. Chumbi Flores W.R. Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF -Mutant Metastatic Non-Small Cell Lung Cancer Clin. Cancer Res. 2020 26 6242 6253 10.1158/1078-0432.CCR-20-1037 32859654

73. Karoulia Z. Wu Y. Ahmed T.A. Xin Q. Bollard J. Krepler C. Wu X. Zhang C. Bollag G. Herlyn M. An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling Cancer Cell 2016 30 485 498 10.1016/j.ccell.2016.06.024 27523909 PMC5021590

74. Okaniwa M. Hirose M. Arita T. Yabuki M. Nakamura A. Takagi T. Kawamoto T. Uchiyama N. Sumita A. Tsutsumi S. Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: Design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives J. Med. Chem. 2013 56 6478 6494 10.1021/jm400778d 23906342

75. Blumenschein G.R. Saintigny P. Liu S. Kim E.S. Tsao A.S. Herbst R.S. Alden C. Lee J.J. Tang X. Stewart D.J. Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial Clin. Cancer Res. 2013 19 6967 6975 10.1158/1078-0432.CCR-12-1818 24166906 PMC3905243

76. Paz-Ares L. Hirsh V. Zhang L. de Marinis F. Yang J.C. Wakelee H.A. Seto T. Wu Y.L. Novello S. Juhász E. Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial: A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens J. Thorac. Oncol. 2015 10 1745 1753 10.1097/JTO.0000000000000693 26743856

77. Wang W.L. Tang Z.H. Xie T.T. Xiao B.K. Zhang X.Y. Guo D.H. Wang D.X. Pei F. Si H.Y. Zhu M. Efficacy and safety of sorafenib for advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials Asian Pac. J. Cancer Prev. 2014 15 5691 5696 10.7314/APJCP.2014.15.14.5691 25081687

78. Shin S. Lee J. Kim T. Kim J. Kim Y. Hong Y. Kim S. A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion J. Clin. Oncol. 2021 39 3007 10.1200/JCO.2021.39.15_suppl.3007

79. de Braud F. Dooms C. Heist R.S. Lebbe C. Wermke M. Gazzah A. Schadendorf D. Rutkowski P. Wolf J. Ascierto P.A. Initial Evidence for the Efficacy of Naporafenib in Combination with Trametinib in NRAS-Mutant Melanoma: Results from the Expansion Arm of a Phase Ib, Open-Label Study J. Clin. Oncol. 2023 41 2651 2660 10.1200/JCO.22.02018 36947734

80. Spira A. Gambardella V. Kato S. Perez C. Mckean M. Cao M. Kim R. Chen C. Abstract CT032: Trials in progress: A global phase 1/1b clinical trial evaluating exarafenib (KIN-2787), a highly selective pan-RAF inhibitor, in adult patients with BRAF-altered solid tumors and NRAS mutant melanoma Cancer Res. 2023 83 CT032 10.1158/1538-7445.AM2023-CT032

81. Sullivan R.J. Hollebecque A. Flaherty K.T. Shapiro G.I. Rodon Ahnert J. Millward M.J. Zhang W. Gao L. Sykes A. Willard M.D. A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer Mol. Cancer Ther. 2020 19 460 467 10.1158/1535-7163.MCT-19-0681 31645440

82. Piha-Paul S. Nagpal S. Weise A. Braiteh F. Chen C. Huang C. Liu W. Hu Y. Yang Z. Tsai K. A phase 1, multicenter, open-label study of a new BRAF inhibitor ABM-1310 in adult patients (pts) with BRAFv600 -mutated solid tumors J. Clin. Oncol. 2023 41 3098 10.1200/JCO.2023.41.16_suppl.3098

83. Beck J. McKean M. Gadgeel S. Bowles D. Haq R. Yaeger R. Taylor M. Maity A. Drescher S. A phase 1, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of PF-07799933 (ARRY-440) as a single agent and in combination therapy in participants 16 years and older with advanced solid tumors with BRAF alterations J. Clin. Oncol. 2023 41 TPS3164 10.1200/JCO.2023.41.16_suppl.TPS3164

84. Shi Y. Han X. Zhao Q. Zheng Y. Chen J. Yu X. Fang J. Liu Y. Huang D. Liu T. Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: An open-label, single-arm, multicenter, phase I study Exp. Hematol. Oncol. 2024 13 60 10.1186/s40164-024-00528-0 38867257 PMC11167782

85. Rasco D.W. Medina T. Corrie P. Pavlick A.C. Middleton M.R. Lorigan P. Hebert C. Plummer R. Larkin J. Agarwala S.S. Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma Cancer Chemother. Pharmacol. 2023 92 15 28 10.1007/s00280-023-04544-5 37219686 PMC10261210

86. Prasad M. Zorea J. Jagadeeshan S. Shnerb A.B. Mathukkada S. Bouaoud J. Michon L. Novoplansky O. Badarni M. Cohen L. MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer J. Immunother. Cancer 2022 10 e003917 10.1136/jitc-2021-003917 35292516 PMC8928405

87. Ramalingam S. Fakih M. Strickler J. Govindan R. Li B. Goldberg S. Gandara D. Burns T. Barve M. Shu C. Abstract P05-01: A phase 1b study evaluating the safety and efficacy of sotorasib, a KRAS G12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors Mol. Cancer Ther. 2021 20 P05-01 10.1158/1535-7163.TARG-21-P05-01

88. Reuss J. Gandhi S. Spigel D. Janne P. Paz-Ares L. Gadgeel S. Patel J. Passiglia F. Spira A. RAMP 202: A phase 2 study of avutometinib (VS-6766) ± defactinib, in patients with advanced KRAS G12V mutant non–small cell lung cancer (NSCLC) J. Clin. Oncol. 2023 41 9100 10.1200/JCO.2023.41.16_suppl.9100

89. Awad M. Goldschmidt J. Spira A. Malhotra R. Yorio J. Bhambhani V. Cheng Y. Lee P. Govidan R. Abstract C026: Initial safety, pharmacokinetics, and recommended Phase 2 dose from RAMP 203: A Phase 1/2 study of Avutometinib + Sotorasib in KRAS G12C Mutant Non-Small Cell Lung Cancer Mol. Cancer Ther. 2023 22 C026 10.1158/1535-7163.TARG-23-C026

90. Minchom A. Perez V. Morton C. Manickavasagar T. Nintos G. Lai-Kwon J. Guo C. Tunariu N. Parker T. Phase I trial of the RAF/MEK clamp VS-6766 in combination with everolimus using an intermittent schedule with expansion in NSCLC across multiple KRAS variants J. Clin. Oncol. 2022 40 9018 10.1200/JCO.2022.40.16_suppl.9018

91. Della Corte C.M. Barra G. Ciaramella V. Di Liello R. Vicidomini G. Zappavigna S. Luce A. Abate M. Fiorelli A. Caraglia M. Antitumor activity of dual blockade of PD-L1 and MEK in NSCLC patients derived three-dimensional spheroid cultures J. Exp. Clin. Cancer Res. 2019 38 253 10.1186/s13046-019-1257-1 31196138 PMC6567578

92. Lee J.W. Zhang Y. Eoh K.J. Sharma R. Sanmamed M.F. Wu J. Choi J. Park H.S. Iwasaki A. Kaftan E. The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer J. Thorac. Oncol. 2019 14 1046 1060 10.1016/j.jtho.2019.02.004 30771521 PMC6542636

93. Hellmann M.D. Kim T.W. Lee C.B. Goh B.C. Miller W.H. Oh D.Y. Jamal R. Chee C.E. Chow L.Q.M. Gainor J.F. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors Ann. Oncol. 2019 30 1134 1142 10.1093/annonc/mdz113 30918950 PMC6931236

94. Theriau C. Feng J. Eng L. Shepherd F. DeCarolis M. Glenns V. Kulkarni S. VanderMeer R. Zurawska-Fortin U. Hao D. Abstract CT206: A phase I study of binimetinib, a MEK inhibitor, in combination with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) Cancer Res. 2023 83 CT206 10.1158/1538-7445.AM2023-CT206

95. Theriau C. Feng J. Eng L. Shepherd F. De Carolis M. Glenns V. Kulkarni S. Vandermeer R. Zurawska-Fortin U. Hao D. A phase I study of binimetinib, a MEK inhibitor, in combination with pembrolizumab in patients with advanced non-small cell lung cancer ( NCT03991819 ) Ann. Oncol. 2024 9 (Suppl. S3) 1 53 10.1016/j.esmoop.2024.102650

96. Ferrucci P.F. Di Giacomo A.M. Del Vecchio M. Atkinson V. Schmidt H. Schachter J. Queirolo P. Long G.V. Stephens R. Svane I.M. KEYNOTE-022 part 3: A randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF —Mutant melanoma J. Immunother. Cancer 2020 8 e001806 10.1136/jitc-2020-001806 33361337 PMC7768966

97. Zimmer L. Livingstone E. Krackhardt A. Schultz E.S. Göppner D. Assaf C. Trebing D. Stelter K. Windemuth-Kieselbach C. Ugurel S. Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAFV600 mutant melanoma: Safety and tolerability results from the phase I IMMU-TARGET trial Eur. J. Cancer 2021 158 72 84 10.1016/j.ejca.2021.09.011 34655839

98. Shi F. Telesco S.E. Liu Y. Radhakrishnan R. Lemmon M.A. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation Proc. Natl. Acad. Sci. USA 2010 107 7692 7697 10.1073/pnas.1002753107 20351256 PMC2867849

99. Mishra R. Patel H. Alanazi S. Yuan L. Garrett J.T. HER3 signaling and targeted therapy in cancer Oncol. Rev. 2018 12 355 10.4081/oncol.2018.355 30057690 PMC6047885

100. Manickavasagar T. Yuan W. Carreira S. Gurel B. Miranda S. Ferreira A. Crespo M. Riisnaes R. Baker C. O'Brien M. HER3 expression and MEK activation in non-small-cell lung carcinoma Lung Cancer Manag. 2021 10 LMT48 10.2217/lmt-2020-0031 34084213 PMC8162178

101. Lyu H. Han A. Polsdofer E. Liu S. Liu B. Understanding the biology of HER3 receptor as a therapeutic target in human cancer Acta Pharm. Sin. B 2018 8 503 510 10.1016/j.apsb.2018.05.010 30109175 PMC6090011

102. Liu X. Liu S. Lyu H. Riker A.I. Zhang Y. Liu B. Development of Effective Therapeutics Targeting HER3 for Cancer Treatment Biol. Proced. Online 2019 21 5 10.1186/s12575-019-0093-1 30930695 PMC6425631

103. Baselga J. Swain S.M. Novel anticancer targets: Revisiting ERBB2 and discovering ERBB3 Nat. Rev. Cancer 2009 9 463 475 10.1038/nrc2656 19536107

104. Yi E.S. Harclerode D. Gondo M. Stephenson M. Brown R.W. Younes M. Cagle P.T. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas Mod. Pathol. 1997 10 142 148 9127320

105. Gandullo-Sánchez L. Ocaña A. Pandiella A. HER3 in cancer: From the bench to the bedside J. Exp. Clin. Cancer Res. 2022 41 310 10.1186/s13046-022-02515-x 36271429 PMC9585794

106. Chen Q. Jia G. Zhang X. Ma W. Targeting HER3 to overcome EGFR TKI resistance in NSCLC Front. Immunol. 2023 14 1332057 10.3389/fimmu.2023.1332057 38239350 PMC10794487

107. Choi B. Cha M. Eun G.S. Lee D.H. Lee S. Ehsan M. Chae P.S. Heo W.D. Park Y. Yoon T.Y. Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers Elife 2020 9 e53934 10.7554/eLife.53934 32267234 PMC7176432

108. Gala K. Chandarlapaty S. Molecular pathways: HER3 targeted therapy Clin. Cancer Res. 2014 20 1410 1416 10.1158/1078-0432.CCR-13-1549 24520092 PMC3977203

109. Sergina N.V. Rausch M. Wang D. Blair J. Hann B. Shokat K.M. Moasser M.M. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3 Nature 2007 445 437 441 10.1038/nature05474 17206155 PMC3025857

110. Amin D.N. Sergina N. Ahuja D. McMahon M. Blair J.A. Wang D. Hann B. Koch K.M. Shokat K.M. Moasser M.M. Resiliency and vulnerability in the HER2-HER3 tumorigenic driver Sci. Transl. Med. 2010 2 16ra17 10.1126/scitranslmed.3000389 PMC3033659 20371474

111. Yonesaka K. Hirotani K. Kawakami H. Takeda M. Kaneda H. Sakai K. Okamoto I. Nishio K. Jänne P.A. Nakagawa K. Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib Oncogene 2016 35 878 886 10.1038/onc.2015.142 25961915

112. Yu H.A. Goto Y. Hayashi H. Felip E. Chih-Hsin Yang J. Reck M. Yoh K. Lee S.H. Paz-Ares L. Besse B. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy J. Clin. Oncol. 2023 41 5363 5375 10.1200/JCO.23.01476 37689979 PMC10713116

113. Cejalvo J.M. Jacob W. Fleitas Kanonnikoff T. Felip E. Navarro Mendivil A. Martinez Garcia M. Taus Garcia A. Leighl N. Lassen U. Mau-Soerensen M. A phase Ib/II study of HER3-targeting lumretuzumab in combination with carboplatin and paclitaxel as first-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer ESMO Open 2019 4 e000532 10.1136/esmoopen-2019-000532 31423336 PMC6678014

114. Li X. Yao J. Qu C. Luo L. Li B. Zhang Y. Zhu Z. Qiu Y. Hua H. DB-1310, an ADC comprised of a novel anti-HER3 antibody conjugated to a DNA topoisomerase I inhibitor, is highly effective for the treatment of HER3-positive solid tumors J. Transl. Med. 2024 22 362 10.1186/s12967-024-05133-7 38632563 PMC11022355

115. Janne P. Mostillo J. Shrestha P. Zhang R. Fan P. Cantero F. Phase 1 study of patritumab deruxtecan (HER3-DXd; U3-1402) in combination with osimertinib in patients with advanced EGFR -mutated NSCLC J. Clin. Oncol. 2022 40 TPS3161 10.1200/JCO.2022.40.16_suppl.TPS3161

116. Zhao Y. Zhang L. Fang W. Yang Y. Huang Y. Zou W. Wang Z. Ding M. Peng Y. SI-B001 plus chemotherapy in patients with locally advanced or metastatic EGFR/ALK wild-type non-small cell lung cancer: A phase II, multicenter, open-label study J. Clin. Oncol. 2023 41 9025 10.1200/JCO.2023.41.16_suppl.9025

117. Rikitake Y. Mandai K. Takai Y. The role of nectins in different types of cell-cell adhesion J. Cell Sci. 2012 125 3713 3722 10.1242/jcs.099572 23027581

118. Boylan K.L. Buchanan P.C. Manion R.D. Shukla D.M. Braumberger K. Bruggemeyer C. Skubitz A.P. The expression of Nectin-4 on the surface of ovarian cancer cells alters their ability to adhere, migrate, aggregate, and proliferate Oncotarget 2017 8 9717 9738 10.18632/oncotarget.14206 28038455 PMC5354766

119. Bouleftour W. Guillot A. Magne N. The Anti-Nectin 4: A Promising Tumor Cells Target. A Systematic Review Mol. Cancer Ther. 2022 21 493 501 10.1158/1535-7163.MCT-21-0846 35131876

120. Sethy C. Goutam K. Nayak D. Pradhan R. Molla S. Chatterjee S. Rout N. Wyatt M.D. Narayan S. Kundu C.N. Clinical significance of a pvrl 4 encoded gene Nectin-4 in metastasis and angiogenesis for tumor relapse J. Cancer Res. Clin. Oncol. 2020 146 245 259 10.1007/s00432-019-03055-2 31617074 PMC11804762

121. Challita-Eid P.M. Satpayev D. Yang P. An Z. Morrison K. Shostak Y. Raitano A. Nadell R. Liu W. Lortie D.R. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models Cancer Res. 2016 76 3003 3013 10.1158/0008-5472.CAN-15-1313 27013195

122. Muro K. Feinstein T. Baranda J. Bonta I. Kitazono S. Gersten T. Gandhi L. Kudo T. Kaplan J. Enfortumab vedotin (EV) in non-squamous and squamous non–small cell lung cancer (NSCLC) cohorts of EV-202 J. Clin. Oncol. 2024 42 8585 10.1200/JCO.2024.42.16_suppl.8585

123. Rigby M. Bennett G. Chen L. Mudd G.E. Harrison H. Beswick P.J. Van Rietschoten K. Watcham S.M. Scott H.S. Brown A.N. BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors Mol. Cancer Ther. 2022 21 1747 1756 10.1158/1535-7163.MCT-21-0875 36112771 PMC9940631

124. Tamura N. Fujiwara Y. Hashimoto T. Shiraishi H. Kitano S. Shimizu T. Kuwano K. Yamamoto N. Motoi N. Correlation between the expression of folate receptor alpha (FRα) and clinicopathological features in patients with lung adenocarcinoma Lung Cancer 2020 145 152 157 10.1016/j.lungcan.2020.05.002 32450493

125. O’Shannessy D.J. Somers E.B. Smale R. Fu Y.S. Expression of folate receptor-α (FRA) in gynecologic malignancies and its relationship to the tumor type Int. J. Gynecol. Pathol. 2013 32 258 268 10.1097/PGP.0b013e3182774562 23518909

126. Necela B.M. Crozier J.A. Andorfer C.A. Lewis-Tuffin L. Kachergus J.M. Geiger X.J. Kalari K.R. Serie D.J. Sun Z. Moreno-Aspitia A. Folate receptor-α (FOLR1) expression and function in triple negative tumors PLoS ONE 2015 10 e0122209 10.1371/journal.pone.0122209 25816016 PMC4376802

127. Yazaki S. Kojima Y. Yoshida H. Takamizawa S. Kitadai R. Nishikawa T. Shimoi T. Sudo K. Saito A. Okuma H.S. High expression of folate receptor alpha is associated with poor prognosis in patients with cervical cancer J. Gynecol. Oncol. 2022 33 e82 10.3802/jgo.2022.33.e82 36245230 PMC9634091

128. OShannessy D.J. Yu G. Smale R. Fu Y.S. Singhal S. Thiel R.P. Somers E.B. Vachani A. Folate receptor alpha expression in lung cancer: Diagnostic and prognostic significance Oncotarget 2012 3 414 425 10.18632/oncotarget.519 22547449 PMC3380576

129. Shimizu T. Fujiwara Y. Yonemori K. Koyama T. Sato J. Tamura K. Shimomura A. Ikezawa H. Nomoto M. Furuuchi K. First-in-Human Phase 1 Study of MORAb-202, an Antibody-Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α-Positive Advanced Solid Tumors Clin. Cancer Res. 2021 27 3905 3915 10.1158/1078-0432.CCR-20-4740 33926914

130. Huttenlocher A. Horwitz A.R. Integrins in cell migration Cold Spring Harb. Perspect. Biol. 2011 3 a005074 10.1101/cshperspect.a005074 21885598 PMC3181029

131. Cooper J. Giancotti F.G. Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance Cancer Cell 2019 35 347 367 10.1016/j.ccell.2019.01.007 30889378 PMC6684107

132. Derynck R. Zhang Y.E. Smad-dependent and Smad-independent pathways in TGF-beta family signalling Nature 2003 425 577 584 10.1038/nature02006 14534577

133. Chung J. Kim T.H. Integrin-dependent translational control: Implication in cancer progression Microsc. Res. Tech. 2008 71 380 386 10.1002/jemt.20566 18300291

134. Akhurst R.J. Hata A. Targeting the TGFβ signalling pathway in disease Nat. Rev. Drug Discov. 2012 11 790 811 10.1038/nrd3810 23000686 PMC3520610

135. Prud'homme G.J. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations Lab. Invest. 2007 87 1077 1091 10.1038/labinvest.3700669 17724448

136. Ni Y. Soliman A. Joehlin-Price A. Rose P.G. Vlad A. Edwards R.P. Mahdi H. High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition NPJ Precis. Oncol. 2021 5 101 10.1038/s41698-021-00242-8 34921236 PMC8683510

137. Dahmani A. Delisle J.S. TGF-β in T Cell Biology: Implications for Cancer Immunotherapy Cancers 2018 10 194 10.3390/cancers10060194 29891791 PMC6025055

138. Elayadi A.N. Samli K.N. Prudkin L. Liu Y.H. Bian A. Xie X.J. Wistuba I.I. Roth J.A. McGuire M.J. Brown K.C. A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for nonsmall cell lung cancer Cancer Res. 2007 67 5889 5895 10.1158/0008-5472.CAN-07-0245 17575158

139. Zhang Z.Y. Xu K.S. Wang J.S. Yang G.Y. Wang W. Wang J.Y. Niu W.B. Liu E.Y. Mi Y.T. Niu J. Integrin alphanvbeta6 acts as a prognostic indicator in gastric carcinoma Clin. Oncol. (R. Coll. Radiol.) 2008 20 61 66 10.1016/j.clon.2007.09.008 17981018

140. Bengs S. Becker E. Busenhart P. Spalinger M.R. Raselli T. Kasper S. Lang S. Atrott K. Mamie C. Vavricka S.R. β 6-integrin serves as a novel serum tumor marker for colorectal carcinoma Int. J. Cancer 2019 145 678 685 10.1002/ijc.32137 30653264

141. Hazelbag S. Kenter G.G. Gorter A. Dreef E.J. Koopman L.A. Violette S.M. Weinreb P.H. Fleuren G.J. Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival J. Pathol. 2007 212 316 324 10.1002/path.2168 17503414

142. Liu L. He Z. Jiang Z. Liu Z. Zhuang X. Acidity-induced ITGB6 promote migration and invasion of lung cancer cells by epithelial-mesenchymal transition and focal adhesion Exp. Cell Res. 2024 436 113962 10.1016/j.yexcr.2024.113962 38316250

143. Breuss J.M. Gallo J. DeLisser H.M. Klimanskaya I.V. Folkesson H.G. Pittet J.F. Nishimura S.L. Aldape K. Landers D.V. Carpenter W. Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling J. Cell Sci. 1995 108 Pt 6 2241 2251 10.1242/jcs.108.6.2241 7673344

144. Trang T. Mazahreh R. Gosink J. Ulrich M. Olson D. Ubben A. Allred S. Huang L. Hensley K. Treuting P. Abstract 1522: SGN-B6A induces immunogenic cell death as an additional mechanism of action Cancer Res. 2023 83 1522 10.1158/1538-7445.AM2023-1522

145. Peters S. Hollebecque A. Sehgal K. Lopez J. Calvo E. Dowlati A. Bockorny B. Perez C. Sanborn R. Efficacy and safety of sigvotatug vedotin, an investigational ADC, in NSCLC: Updated phase 1 results (SGNB6A-001) J. Clin. Oncol. 2024 42 8521 10.1200/JCO.2024.42.16_suppl.8521

146. Hwang J.W. Cho Y. Bae G.U. Kim S.N. Kim Y.K. Protein arginine methyltransferases: Promising targets for cancer therapy Exp. Mol. Med. 2021 53 788 808 10.1038/s12276-021-00613-y 34006904 PMC8178397

147. Kim H. Ronai Z.A. PRMT5 function and targeting in cancer Cell Stress. 2020 4 199 215 10.15698/cst2020.08.228 32743345 PMC7380451

148. Jing P. Zhao N. Ye M. Zhang Y. Zhang Z. Sun J. Wang Z. Zhang J. Gu Z. Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling Cancer Lett. 2018 427 38 48 10.1016/j.canlet.2018.04.019 29679612

149. Sun M. Hong S. Li W. Wang P. You J. Zhang X. Tang F. Zhang C. MiR-99a regulates ROS-mediated invasion and migration of lung adenocarcinoma cells by targeting NOX4 Oncol. Rep. 2016 35 2755 2766 10.3892/or.2016.4672 26986073

150. Pal S. Vishwanath S.N. Erdjument-Bromage H. Tempst P. Sif S. Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes Mol. Cell Biol. 2004 24 9630 9645 10.1128/MCB.24.21.9630-9645.2004 15485929 PMC522266

151. Fu T. Lv X. Kong Q. Yuan C. A novel SHARPIN-PRMT5-H3R2me1 axis is essential for lung cancer cell invasion Oncotarget 2017 8 54809 54820 10.18632/oncotarget.18957 28903384 PMC5589623

152. Zhang H. Chen Z.H. Savarese T.M. Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-alpha1, interferon-beta1, and other 9p21 markers in human malignant cell lines Cancer Genet. Cytogenet. 1996 86 22 28 10.1016/0165-4608(95)00157-3 8616780

153. Marjon K. Cameron M.J. Quang P. Clasquin M.F. Mandley E. Kunii K. McVay M. Choe S. Kernytsky A. Gross S. MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis Cell Rep. 2016 15 574 587 10.1016/j.celrep.2016.03.043 27068473

154. Stopa N. Krebs J.E. Shechter D. The PRMT5 arginine methyltransferase: Many roles in development, cancer and beyond Cell Mol. Life Sci. 2015 72 2041 2059 10.1007/s00018-015-1847-9 25662273 PMC4430368

155. Shilo K. Wu X. Sharma S. Welliver M. Duan W. Villalona-Calero M. Fukuoka J. Sif S. Baiocchi R. Hitchcock C.L. Cellular localization of protein arginine methyltransferase-5 correlates with grade of lung tumors Diagn. Pathol. 2013 8 201 10.1186/1746-1596-8-201 24326178 PMC3933389

156. Aggarwal P. Vaites L.P. Kim J.K. Mellert H. Gurung B. Nakagawa H. Herlyn M. Hua X. Rustgi A.K. McMahon S.B. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase Cancer Cell 2010 18 329 340 10.1016/j.ccr.2010.08.012 20951943 PMC2957477

157. Jeon J.Y. Lee J.S. Park E.R. Shen Y.N. Kim M.Y. Shin H.J. Joo H.Y. Cho E.H. Moon S.M. Shin U.S. Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells Oncol. Rep. 2018 40 536 544 10.3892/or.2018.6402 29749478

158. Wu Y. Wang Z. Zhang J. Ling R. Elevated expression of protein arginine methyltransferase 5 predicts the poor prognosis of breast cancer Tumour Biol. 2017 39 1010428317695917 10.1177/1010428317695917 28381188

159. Ibrahim R. Matsubara D. Osman W. Morikawa T. Goto A. Morita S. Ishikawa S. Aburatani H. Takai D. Nakajima J. Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition Hum. Pathol. 2014 45 1397 1405 10.1016/j.humpath.2014.02.013 24775604

160. Han X. Li R. Zhang W. Yang X. Wheeler C.G. Friedman G.K. Province P. Ding Q. You Z. Fathallah-Shaykh H.M. Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro J. Neuroon. 2014 118 61 72 10.1007/s11060-014-1419-0 PMC4076054 24664369

161. Győrffy B. Surowiak P. Budczies J. Lánczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer PLoS ONE 2013 8 e82241 10.1371/journal.pone.0082241 24367507 PMC3867325

162. Brehmer D. Beke L. Wu T. Millar H.J. Moy C. Sun W. Mannens G. Pande V. Boeckx A. van Heerde E. Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity Mol. Cancer Ther. 2021 20 2317 2328 10.1158/1535-7163.MCT-21-0367 34583982 PMC9398174

163. Ahnert J. Perez C. Wong K. Maitland M. Tsai F. Berlin J. Liao K. Wang I. Markovtsova L. PF-06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: A phase 1 dose escalation study J. Clin. Oncol. 2021 39 3019 10.1200/JCO.2021.39.15_suppl.3019

164. Siu L. Rasco D. Vinay S. Romano P. Menis J. Opdam F. Heinhuis K. Egger J. Gorman S. METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumors Ann. Oncol. 2019 30 v159 v193 10.1093/annonc/mdz244

165. Engstrom L.D. Aranda R. Waters L. Moya K. Bowcut V. Vegar L. Trinh D. Hebbert A. Smith C.R. Kulyk S. MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer Cancer Discov. 2023 13 2412 2431 10.1158/2159-8290.CD-23-0669 37552839 PMC10618744

166. Cottrell K.M. Briggs K.J. Whittington D.A. Jahic H. Ali J.A. Davis C.B. Gong S. Gotur D. Gu L. McCarren P. Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers J. Med. Chem. 2024 67 6064 6080 10.1021/acs.jmedchem.4c00133 38595098 PMC11056935

167. Villalona-Calero M. Patnaik A. Maki R. O’Neil B. Abbruzzese J. Dagogo-Jack I. Devarakonda S. Wahlroos S. Lin C. Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors J. Clin. Oncol. 2022 40 TPS3167 10.1200/JCO.2022.40.16_suppl.TPS3167

168. Li S. de Camargo Correia G.S. Wang J. Manochakian R. Zhao Y. Lou Y. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer Cancers 2023 15 2899 10.3390/cancers15112899 37296863 PMC10251928

169. Russo A. Cardona A.F. Caglevic C. Manca P. Ruiz-Patiño A. Arrieta O. Rolfo C. Overcoming TKI resistance in fusion-driven NSCLC: New generation inhibitors and rationale for combination strategies Transl. Lung Cancer Res. 2020 9 2581 2598 10.21037/tlcr-2019-cnsclc-06 33489820 PMC7815353