Oncogenic influences of neurotrophin receptors: Shedding light on Trk biology.

INTRODUCTION

Tropomyosin receptor kinases (TrkA, TrkB, and TrkC) are a family of receptor tyrosine kinases that play a pivotal role in neurodevelopment, differentiation, survival, and synaptic plasticity. The receptors were initially characterized as high-affinity receptors for neurotrophins, where binding initiates key cellular survival signaling cascades, 1 but have since emerged as critical players in driving potent oncogenic signaling. 2

The Trk receptor encoding genes— NTRK1 , NTRK2 , and NTRK3 —were first known for their roles in neural and developmental processes. NTRK1 encodes TrkA, which binds nerve growth factor (NGF). 3 Similarly, NTRK2 and NTRK3 , respectively, encode TrkB and TrkC. TrkB binds brain-derived neurotrophic factor (BDNF), and TrkC binds neurotrophin-3 (NT3) ( Figure 1 ). NT-3 binds all three receptors but exhibits the highest affinity for TrkC. 3 , 4 Binding of neurotrophins to Trk receptors initiates dimerization, leading to tyrosine residue phosphorylation and activation of downstream signaling pathways. Alternative splicing of NTRK genes generates diverse Trk isoforms with distinct ligand affinities, cellular localizations, and signaling outcomes. 3

Disturbances in Trk signaling are associated with impaired neural development and differentiation. Interestingly, impairment of essential cognitive functions and increased vulnerability to psychological disorders has been observed in pediatric cancer survivors, highlighting the clinical relevance of these pathways in neurodevelopment. 5 Moreover, Trk receptors are constitutively expressed in subsets of neurons throughout both the developing and adult central and peripheral nervous systems (CNS and PNS), indicating their sustained role in neuronal maintenance and function. 6

In tumor biology, the dysregulation of Trk signaling is hijacked through changes in expression, splice variants, and gene fusions. Consequently, Trk receptors have become attractive therapeutic targets, with Trk inhibitors showing significant efficacy in treating Trk fusion-positive cancers irrespective of tissue origin. 3 In this review, we explore the role of Trk signaling in neuronal development and mature cells, highlighting recent advances in Trk research and their role in cancer.

TRK RECEPTORS IN EARLY HUMAN DEVELOPMENT AND ADULTHOOD

The key signaling pathways activated downstream of Trk receptors include the Ras/MAPK, PI3K/AKT, and phospholipase Cγ (PLCγ) pathways. Each path contributes to distinct yet interconnected aspects of cellular behavior. The Ras/MAPK and PI3K/AKT signaling pathways are summarized in Figure 2 .

The PLCγ pathway drives synaptogenesis and the formation of functional neural networks during early stages of development. 9 , 10 Upon Trk activation, PLCγ is recruited and activated via phosphorylation. Activated PLCγ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol trisphosphate (IP3) and diacylglycerol (DAG), triggering intracellular calcium release and activation of protein kinase C (PKC). 11 This is essential for activity-dependent synaptic development and fine-tuning of neural circuitry. 3 , 12

Role in neural development

During embryogenesis, Trk receptors are differentially expressed in the developing brain and spinal cord, guiding processes such as axonal pathfinding, dendritic arborization, and synaptogenesis. 9 , 10 TrkA is crucial for the development of nociceptive sensory neurons; mutations or deletions in NTRK1 can result in congenital insensitivity to pain with anhidrosis (CIPA). 13 , 14 BDNF/TrkB signaling is vital for the development of the CNS by influencing cortical layering, hippocampal development, and synaptic refinement. 15 TrkC also contributes to the formation of the proprioceptive sensory neurons and plays a regulatory role in cardiac and musculoskeletal development. 16

Beyond the nervous system

Trk signaling is involved in the differentiation of certain mesodermal and ectodermal derivatives, such as ovaries, the vasculature system, and immune system. 13 Additionally, research suggests that TrkC regulates gonadotrope cell adhesion and motility. 17

The role of Trk receptors through adulthood

In adulthood, mature neurons rely on Trk receptors through both target-derived and autocrine neurotrophin signaling to regulate axonal sprouting and long-term potentiation. 18 Neurotrophin receptors also play a role in the functional integrity of the enteric nervous system. 19

Trk receptors are also capable of ligand-independent activation, specifically through crosstalk with G-protein-coupled receptors (GPCR) such as the adenosine 2A (A2A) receptor. 20 Activation of the A2A receptor induces sustained activation of the PI3K/AKT survival pathway via Trk transactivation, which is distinct from typical GPCR activation that mainly activates the MAPK pathway. 20 As a result, GPCR-mediated Trk activation has neuroprotective implications, as this activation can enhance cell survival in neurons deprived of trophic support. 20 Similarly, activation of Trk receptors via glucocorticoids, such as dexamethasone, also exerts neuroprotective properties by activating the PI3K/AKT signaling pathway and promoting neuronal survival in the absence of trophic support, and relies on both glucocorticoid receptor and Trk receptor activity for its efficacy. 21 However, prolonged activation of Trk receptors leads to their downregulation, suggesting a mechanism that modulates receptor activity beyond sustained activation for continuous growth and renewal. 4 Additionally, transient versus sustained activation of TrkB in cultured neurons can lead to differential cellular and molecular changes. Specifically, in young neurons, acute administration of BDNF in the extracellular space induces dendritic elongation, while transient administration of BDNF promotes dendritic branching. However, in mature neurons with established synaptic connections, transient administration of BDNF facilitates enlargement of spine heads. These studies underscore that dose-dependent activation of Trk receptors can lead to a variety of different cellular functions based on the nature of the cell(s) in question. 22 Lastly, Trk receptors can increase the expression of NGF via transcriptional regulation, suggesting a positive autocrine feedback loop. 23

Furthermore, Trk receptors are essential for regulating the differentiation of adult neural stem cells and progenitor cells into neurons and glial cells. 24 Specifically, studies have shown that BDNF/TRKB.T1 signaling promotes morphological maturation in cortical astrocytes. 24 Additionally, studies assessing BDNF/TRKB signaling in oligodendrocyte progenitor cells (OPCs) determined that conditional deletion of TRKB disrupted OPC proliferation and activity-dependent oligodendrogenesis. 25

Recent studies suggest that Trk receptors interact with insulin signaling pathways, which modulate neurotrophin levels and receptor expression, influencing neurogenesis and gliogenesis. 26 Additionally, electrical stimulation of human neural progenitor cells in conductive nerves upregulates gene expression of neurotrophic factors, providing long-lasting effects on peripheral nerve regeneration and distal nerve reinnervation. 27

TRK SPLICING, FUSIONS, AND CANCER-NERVE CROSSTALK IN CANCER

Trk receptors are highly important in oncology due to their frequent dysregulation ( Table 1 ). Altered expression of Trk receptors can amplify canonical or non-canonical signaling pathways and contribute to cancer progression. Drivers of changes in Trk expression level include point mutations, increases in gene copy number, and mRNA overexpression. 28 Splice variants introduce structural alterations in receptor domains that eliminate or change normal regulatory mechanisms, promoting new signaling activity and further facilitating oncogenic processes. 3 NTRK gene fusions result in hybrid proteins with constitutively active kinase domains ( Figure 3 ), leading to unregulated cancer growth signaling.

The critical involvement of Trk receptors in both neurodevelopment and cancer biology sets the stage for their fundamental role in cancer-nerve crosstalk within the tumor microenvironment. This interaction is most clinically defined by perineural invasion (PNI), a pathological process whereby cancer cells actively infiltrate and proliferate within the layers of the neural sheath. PNI is a poor prognostic factor and a major route for metastasis and local recurrence, especially in highly innervated tumors such as pancreatic, prostate, gastric, and head and neck cancers. 29 Mechanistically, the Trk family and its ligands serve as the essential bridge driving PNI and tumor-induced nerve remodeling through overexpression, and dual Trk signaling on both nerves and the tumor. Trk receptor ligand binding on the nerve fibers drives neurogenesis of new nerve fibers into the tumor. This remodels the local nervous system to fuel tumor growth. On the tumor itself, ligand binding to Trk receptors on cancer cells promotes chemotactic migration and invasive signaling, which provides cancer cells with a “road map” to invade the perineum. 29 What further complicates this crosstalk is the concept of neuron-tumor synapses, by which cancer cells form functional synapses with healthy neurons, thereby hijacking and diverting direct neural input, which promotes proliferation and survival of the cancer. 30 Trk signaling is strongly implicated in maintaining these aberrant connections, and this represents a novel target for interrupting the neural regulation of cancer growth. 29

THE ROLE OF TRK RECEPTOR SIGNALING IN CNS CANCERS

Astrocytoma, medulloblastoma, and glioblastoma

TrkA can either be protumoral or antitumoral. Chernov et al. 31 described NGF treatment to have an additive cytotoxic effect on anaplastic astrocytoma and medulloblastoma cell lines in combination with chemotherapy treatment. 31 Both NGF alone and NGF in combination with either cisplatin or temozolomide altered the expression levels of TrkA and p75, changing the sensitivity of astrocytoma, medulloblastoma, and glioblastoma cells to the treatment’s cytotoxic effects. 31 Yet, each cancer model demonstrated varying sensitivities. Although no mechanistic assays were performed to confirm why this was the case, the variation could have been due to changes in the TrkA/p75 expression ratio, altering its correlation with the cytotoxic effect. 31 In medulloblastoma cells, MYC copy number had a negative correlation with their sensitivity to NGF’s cytotoxic effects, 31 but it is unclear how MYC affects the TrkA signaling pathway and whether there is any direct interaction. Further studies to decipher the relationship between MYC and TrkA would be valuable.

Although there are only novel inferential mechanistic findings associated with NTRK1 induced oncogenesis, there are mechanisms of TRK-inhibitor resistance that have been discovered since the US Food and Drug Administration approval of and increased usage of these inhibitors. Entrectinib-resistant tumor cells in a brain metastasis model acquired the resistance mutation NTRK1-G595R . 32 The second-generation TRK inhibitor repotrectinib targets NTRK1-G595R , but simultaneous ERK and epidermal growth factor receptor (EGFR) activation allowed for repotrectinib resistance. 32 An increase in the EGFR ligand amphiregulin induced a large portion of this activation, but the mechanism behind this increase in ligand production and the remaining ERK activation has yet to be clarified. 32 These findings demonstrate that therapeutic diversification for more potent treatment is necessary. Yet, it is unclear how these NTRK resistance mutations mechanistically alter tumor cell biology and whether they are responsible for additional resistance mechanisms such as the increase in ERK and EGFR activation in this model.

Anaplastic astrocytoma and glioblastoma multiforme (GBM) malignant behavior and resistance to therapy is correlated with overexpression of survival pathways such as Ras/Raf/MEK/ERK and PLCγ1/PKC regulated by the NT3, NT4/TrkB axis. 33 This axis is known to regulate survival and differentiation of neuronal processes. 33 Both pharmacological and small interfering RNA inhibition of TrkB led to apoptosis, 33 but it is unclear whether this was due to cellular necessity for the Trk receptor or if this was specific to the glioma cell lines. In addition, the pan-Trk inhibitory effect of larotrectenib also implicates TrkA and TrkC in these findings. In a similar context, a patient whose recurrent midline pilocytic astrocytoma harbored the unique STRN3-NTRK2 fusion achieved and sustained near-complete radiographic and clinical response with larotrectinib. This success reinforces the imperative for molecular diagnostics in identifying and precisely targeting actionable NTRK fusions in BRAF-negative gliomas. 34

TrkA, TrkB, and TrkC have all been implicated in the RAF/MEK/ERK signaling axis. Schmid et al. 35 utilized various NTRK1/2/3 fusion-driven mouse glioma models to investigate resistance mechanisms that arise from point mutations in the kinase domains. 35 This revealed that phosphorylation of ERK was a persistent phenomenon after treatment with the second-generation TRK inhibitor entrectinib. 35 RAF/MEK/ERK signaling played a critical role in TRK-inhibitor resistance biology, with persistent phosphorylation of ERK arising in both in vitro and in vivo kinase point mutation models. 35 Combination inhibition of both MEK and Trk was able to decrease p -ERK levels in vitro , and each treatment reduced the growth rate of in vivo NTRK fusion gliomas. 35 Beyond unveiling the mechanisms of resistance generation in Trk cancers, this work demonstrates the predictive value that in vitro models can have for NTRK gene-alteration targeting and potential response outcomes with TRK inhibitors.

Several studies have shown a correlation between the expression of NTRK2/TrkB and other growth factor receptors in GBMs and brain metastases. NTRK2 expression is increased in GBM subtypes and is correlated with EGFR expression. Combination inhibition of both TrkB and EGFR showed success in vitro but was unsuccessful in vivo . 36 Pinheiro et al. 36 reported a correlation and functional interaction between EGFR and TrkB that could potentially be therapeutically targeted in glioblastoma. 36 However, simultaneous inhibition of EGFR and TrkB can be both synergistic or antagonistic depending on cell type, 36 which demonstrates the importance of context in Trk biology. TrkB inhibition induced a reduction of cells in S phase, while EGFR inhibition increased cells in G 0 /G 1 phase. 36

In addition, TrkB and the positivity of human epidermal growth factor receptor 2 (HER2) in breast cancer are independently associated with an increased risk for brain metastases, implying a link between TrkB expression and HER2-positive breast cancer. 37 TrkB expression correlated with vascular invasion, increased lymph node metastases, more advanced TNM staging system, and poorer overall survival. 37 Although this correlation is prognostically valuable, deciphering the mechanism behind the associations between these receptors could be valuable.

The expression of TrkB in cancer cells can change their oncogenic phenotypes but, fascinatingly, TrkB is being utilized to change cancer’s architecture and the brain’s architecture using mechanisms of the healthy brain. Taylor et al. investigated the impact of the BDNF/TrkB axis on glioma synapses. They revealed that BDNF/TrkB signaling contributed to neuron-glioma interactions by mediating the magnitude of neuronally induced proliferation of glioma cells through synaptic regulatory processes. 38 BDNF addition to glioma containing hippocampal ex vivo brain slices increased the amplitude of AMPA receptor (AMPAR)-mediated glutamatergic currents in glioma cells by increasing the trafficking of AMPARs to the postsynaptic membrane via the CAMKII Ca 2+ signaling pathway. 38 This increase in amplitude directly promoted an increase in glioma proliferation. 38 In addition, CRISPR knockout of NTRK2 led to a decrease in the number of neuron-glioma synapses. Trk-mediated regulation of tumor synaptic connectivity to surrounding neural tissue is a highly novel area of research.

Although previously mentioned works describe the pathogenesis of the full-length TrkB receptor (TrkB.FL), Pattwell et al. 39 describe the potential of the truncated isoform (TrkB.T1) lacking the kinase domain to play a role in oncogenic pathogenesis. Publicly available patient gene-expression data showed that in low-grade glioma, glioblastoma, and glioma stem cells, the kinase-deficient NTRK2 splice variant, TrkB.T1, is predominant, while in normal brain there is a balanced expression level between TrkB.FL and TrkB.T1. 39 Unlike other works, TrkB.FL was associated with better prognosis for glioblastoma and low-grade glioma. 39 Through the generation of an antibody targeted to TrkB.T1’s unique intracellular domain, its localization in normal brain and glioma was identified with a vesicular and punctate distribution and a vastly diffuse and more intense distribution, respectively. 39 In addition, platelet-derived growth factor (PDGF) gliomas generated in vivo using the RCAS/tv-a system experienced enhanced formation when created with TrkB.T1, leading to a decrease in survival. 39 Although PDGF is not a canonical ligand of TrkB, TrkB.T1 expressing 3T3/tv-a cells showed increased phosphorylation of downstream signaling pathways implicated in gliomagenesis including STAT3, AKT, S6, and ERK post PDGF stimulation. 39 The mechanism behind the signaling coupling between PDGFR-b and TrkB.T1 is still unclear; however, Gene Ontology term analysis on the patient transcript data and glioma stem cells point to TrkB.T1-associated endocytic and vesicular processes that may influence the degradation or recycling of either receptor. 39 Yet, simple transfection of TrkB.T1 alone in neural stem cells led to an increase in expression of genes pertaining to PI3K and AKT signaling, 39 making it unclear whether TrkB.T1 has an independent and additive mechanism on these protumoral pathways. To support this work, Lombardi et al. 40 show that TrkB isoforms correlate with increased metastases to the CNS. In non-small cell lung cancer (NSCLC), TrkB and truncated variant TrkB.T1 expression levels correlate with CNS metastases from lung cancer. 40

The functional activity of Trk isoforms is important evidence that underscores the importance of associating specific cancer mechanisms with specific isoforms. This stark difference in correlation with poor prognosis between the truncated TrkB isoform and the full-length receptor is also represented in their influences at critical developmental time points. During early organogenesis, TrkB.FL is mainly expressed in the CNS, while TrkB.T1 has diffuse expression across many different organs. 41 Using their RCAS/tv-a mouse model, Pattwell et al. 41 generated a variety of tumors throughout the body at the TrkB.T1 embryonic sites using a combination of a short hairpin for PTEN and TrkB.T1. 41 Given the diverse incidence of NTRK fusions and their aberrant mechanism of constitutively activating the Trks, it is of no surprise that the field focuses strongly on discovering their incidence. In vitro studies have shown that cells from infants (<3 years old) diagnosed with high-grade glioma (HGG) expressing either ETV6-NTRK3 or TPM3-NTRK1 fusion are sensitive to crizotinib, entrectinib, milciclib—three small-molecule inhibitors of TRKA/B/C—in comparison to cells from fusion-negative infants with HGG. These findings were underscored by clinical work showing that two patients with HGG harboring the ETV6-NTRK3 fusion responded to crizotinib (as well as larotrectinib, another NTRK inhibitor), with no recurrence 12 months post treatment. These novel works emphasize not only the need to identify NTRK fusions in patients with glioma but also the importance of deciphering the specific mechanisms associated with each Trk isoform to better understand how to treat current and future patients. 42

A recent finding includes the discovery of a circle RNA (circRNA) capable of encoding a 243-amino-acid NTRK2 protein called NTRK2–243aa. CircRNAs may have a regulatory role in tumorigenesis and development. NTRK2–243aa had a negative correlation with GBM grade. When overexpressed, NTRK2–243aa inhibited glucose uptake, lactose uptake, extracellular acidification rate, and cell proliferation. It also downregulated PAX5 expression, which was positively correlated with GBM grade. 43

These novel works emphasize the importance of deciphering the specific mechanisms associated with each Trk isoform. Filling these gaps of knowledge would be a source of clarity for inconsistencies in the field, such as TrkA’s protumoral versus antitumoral activity that may partially be attributed to its splice variants.

THE ROLE OF TRK RECEPTOR SIGNALING IN PNS CANCERS

Neuroblastoma

Neuroblastoma is the most frequent extracranial pediatric cancer originating from immature sympathoadrenal progenitor cells that have failed to differentiate into sympathetic neurons or adrenal chromaffin cells. Therefore, various studies have utilized neuroblastoma cells as a model to study the process of neuronal or adrenal chromaffin differentiation. Given that Trk proteins have been shown to play a vital role in both sympathetic and parasympathetic development with emphasis on its role in differentiation, various studies have been conducted to uncover their role in neuroblastoma.

Although TrkA expression is typically associated with less aggressive forms of neuroblastoma and neuroblastoma regression, TrkAIII, an alternative splice variant of TrkA, has been shown to play an oncogenic role in neuroblastoma. 44 TrkAIII is characterized by exon 6–7 skipping, resulting in deletion of the D4 immunoglobulin (Ig)-like domain, which allows full-length TrkA to be expressed extracellularly. 44 As a consequence, TrkAIII remains intracellularly, exhibiting spontaneous activation that induces chronic activation of the PI3K/AKT/nuclear factor κB (NF-κB) pathway and ultimately promoting proliferation. 45 , 46

In contrast to full-length TrkA, TrkB is associated with more aggressive forms of neuroblastoma and lower survival prognosis. 47 Mechanistically, it has been shown in NB-1643, a neuroblastoma cell line, that BDNF leads to autophosphorylation of TrkB, which conferred resistance to cisplatin and increased survival of NB-1643 in low-serum conditions via the PI3K pathway. 48 , 49 Lastly, TrkC, which is typically associated with less aggressive forms of neuroblastoma with expression positively correlated to TrkA expression in non-MYCN-amplified neuroblastoma cells, 50 has recently been shown to play an oncogenic role in MYCN-amplified neuroblastoma cells. Specifically, it has been shown that activation of TrkC in non-MYCN-amplified neuroblastoma cells induced cellular differentiation via protein kinase A (PKA) signaling; conversely, TrkC activation in MYCN-amplified cells resulted in enhanced proliferation. 51 Further dissection of this mechanism revealed that MYCN reduces expression of PKA-associated genes and ultimately abrogates TrkC-induced differentiation in neuroblastoma. 51 Through exogenous activation of PKA via db-cAMP treatment in MYCN-amplified neuroblastoma cells, TrkC-induced differentiation was restored, highlighting the TrkC/PKA signaling axis as a potential therapeutic option to consider when treating MYCN-amplified neuroblastomas. 51

Studies elucidating the different oncogenic roles played by Trk proteins in neuroblastoma have led to various efforts regarding the development of Trk inhibitors and their application(s) in various cancers in addition to neuroblastoma. Additionally, these studies highlight Trk-associated downstream signaling pathways as another node for therapeutic potential in neuroblastoma, suggesting the repurposing of certain drugs that are typically used in adult malignancies to treat more aggressive forms of neuroblastoma.

THE ROLE OF TRK RECEPTOR SIGNALING IN NON-NERVOUS SYSTEM CANCERS

The case for a mechanistic classification of non-neural cancers

Trk receptor signaling in the PNS has been studied primarily through tumors that originate directly from neural or nerve-derived structures, such as schwannomas, neurofibromas, neuroblastomas, and malignant peripheral nerve sheath tumors. This framework has significantly advanced our understanding; furthermore, a review of the literature demonstrates that Trk receptor signaling also critically underlies tumor biology through perineural invasion and neurotrophin interactions in malignancies from non-neural, but neural-adjacent, origin. In fact, multiple studies found that in various carcinoma and sarcoma subtypes, increased expression of TrkA, TrkB, and TrkC was correlated with PNI, suggesting that Trk signaling contributes to aggressive and nerve-infiltrative behavior of these tumors despite their non-neural origin. 52 , 53

One of the most striking patterns among NTRK-rearranged tumors is the presence of markers traditionally associated with neural crest or mesenchymal lineages. Many non-neural tumors exhibit CD34/S100 co-expression in addition to positive pan-Trk immunohistochemistry, reflecting hybrid mesenchymal-neural differentiation states characteristic of neural-derived tumors. Specifically, CD34 is well established as a progenitor cell marker expressed in mesenchymal stromal cells, while S100 is typically expressed in Schwann and neural-crest lineages. 54 , 55 A review of the literature reveals that this co-expression pattern also appears in a multitude of Trk-driven non-neural cancers, hinting that a combination of Trk signaling and reactivation of developmental programs contributes to the stem-like and migratory phenotypes reminiscent of neural crest biology. It is critical to note that many cases exist in which pan-Trk positivity occurs without co-expression of S100 or CD34, underscoring the greater emphasis for molecular rather than immunohistochemical classifications. Therefore, we propose a mechanistic classification of cancer subtypes that emphasizes shared oncogenic hallmarks, such as NTRK fusions, overexpression, polysomy, and mechanism hijacking.

Sarcomas

The molecular diversity of NTRK fusions is well documented in the literature. One of the most notable soft-tissue NTRK fusions is the ETV6 : NTRK3 fusion occurring in a spectrum of sarcoma subtypes, including infantile fibrosarcoma and adult-type renal fibrosarcoma. 56 Similarly, congenital mesoblastic nephromas frequently harbor NTRK fusions, with reported incidences exceeding 90%. 3

Khuong-Quang et al. 57 reported three cases of SPECC1L : NTRK fusions in congenital infantile fibrosarcoma ( NTRK3 ), anaplastic astrocytoma ( NTRK2 ), and a low-grade neuroepithelial tumor ( NTRK2 ), demonstrating that SPECC1L can act as a recurring fusion partner across NTRK family members and diverse tumor types in both mesenchymal and neural linages. 57 Further, this fusion was sufficient to drive cytokine-independent tumor survival. In a distinct context, Zhou et al. 58 described a rare, novel case of a SPECC1L : NTRK3 in a thoracic spine spindle-cell sarcoma. 58 Further, SPECC1L-NTRK3 fusions were described in a cervical sarcoma case, exhibiting loss of SMARCB1 protein driven by the fusion. 59

Further evidence shows how rarer NTRK presentations can drive similar oncogenic programs. 60 The study identified two spindle-cell sarcoma cases of NTRK1 fusions, specifically CPSF6 : NTRK1 and TPM3 : NTRK1 , in tumors with infantile fibrosarcoma-like morphology but arising in unexpected anatomic sites, such as the genitourinary system. These tumors, although morphologically identical to ETV6 : NTRK3 -driven infantile fibrosarcoma, rely on TrkA signaling instead of TrkC. This cross-tissue convergence is further shown in a recent report of NTRK -rearranged spindle-cell neoplasms ( LMNA : NTRK1 , TPM3 : NTRK1 , and STRN : NTRK2 fusions) arising in the gastrointestinal tract. 61 Despite their rare locations, these tumors are marked by typical hallmark features of neural differentiation and Trk-driven neoplasms.

Similarly, NTRK1 and NTRK3 fusion partners TPM3 , SPECC1L , and TPR were reported in uterine spindle-cell myxoid sarcomas. 62 In a recent case, 63 a 1-year-old male presented with a cervical spindle-cell tumor, and next-generation sequencing (NGS) confirmed the rare TPR : NTRK1 fusion as the oncogenic driver. This case emphasizes that NGS plays a critical role in complementing immunohistochemistry (IHC) profiling and facilitates accurate classification, as well as informing potential eligibility for targeted therapies. 63

Recent evidence sheds light on some of the mechanistic interplay behind acquired Trk-inhibitor resistance in LMNA : NTRK1 -driven soft-tissue sarcoma. 64 Researchers identified a mechanism of entrectinib resistance involving a loss-of-function mutation in the NF2 tumor-suppressor gene, indicating a functional role for NF2 loss in tumor resistance to Trk-targeted therapies. RNA sequencing revealed upregulation of the MAPK and mTOR/AKT pathways in resistant lines, suggesting that these tumor cells bypass Trk inhibition by activation of alternative tumor survival pathways. As such, the researchers found that the Trk-inhibitor-resistant cells responded to MEK and mTOR inhibitors, showing that using a combination of drugs has the potential to overcome resistance.

LMNA : NTRK1 fusions are also reported in separate cases of lipofibromatosis-like neural tumor that shares features with pigmented dermatofibrosarcoma and low-grade malignant peripheral nerve sheath tumor, while the second case had a non-neural myxoid spindle-cell sarcoma. 65 , 66 Both cases had positive co-expression of CD34/S100 but were negative for SOX10.

A recent case report documents a previously undescribed NUMA1 : NTRK1 fusion in a uterine cervical sarcoma positive for CD34 but negative for S100. 67 The mechanism of action utilizes NUMA protein’s oligomerization domain, when fused to kinase of TrkA, to drive constitutive activation.

Such findings constitute a growing class of tumors that functionally engage Trk signaling not as a marker of neural lineage but as an adaptive oncogenic strategy. Across sarcoma subtypes, NTRK fusions define a distinct molecular class linked by shared signaling, IHC overlap, and cross-lineage mimicry. Despite embryonic and histological variability, these tumors converge on Trk-driven survival mechanisms. CD34/S100 co-expression frequently underlies this mimicry but is insufficient alone for classification, necessitating molecular profiling and NGS for accurate therapeutic direction.

To further emphasize the valuable nature of molecular profiling in informing therapeutic direction, emerging evidence highlights the potential of Trk-targeted therapies in histologically unclassifiable sarcomas. 68 Researchers identified an unclassified mesenchymal malignancy marked by a NTRK1 : KHDRBS1 fusion, in which the patient was able to achieve long-term survival after being treated with a multikinase inhibitor. Despite the lack of histological diagnosis, molecular profiling allowed effective treatment. This case paves the way for classifying such tumors as “ NTRK -omas,” similar to the “ ALK -omas” classification, defining cancer more by molecular alteration than by tissue of origin or morphology.

However, not all NTRK fusion sarcomas present with features of neural mimicry. A novel case of TMTC2 : NTRK3 fusion was recently discovered in undifferentiated high-grade pleomorphic sarcoma, a highly aggressive, poor-prognostic malignancy. 69 IHC showed positive CD34 only in vascular endothelial cells, but negative results with S100 despite strong pan-Trk positivity. In another finding supporting this, Siozopoulou et al. 70 examined ETV6 : NTRK3 in low-grade spindle-cell tumor and TFG : NTRK3 in high-grade spindle-cell tumor and found negative CD34/S100, in sharp contrast to existing literature on TFG : NTRK3 -fused tumors. We see that Trk signaling can indeed operate outside of classical mesenchymal-neural states, highlighting the importance of mechanism-based knowledge in cancer classification.

Interestingly, instances of fusion-driven tumors resembling NTRK -rearranged sarcomas in terms of both morphology and CD34/S100 co-positivity have been documented multiple times in the literature. 71 , 72 These phenocopies are not driven by NTRK fusions but rather by other activating mutations in the MAPK pathway. Another case describes three FGFR1 -rearranged pediatric mesenchymal tumors that share histological overlap with NTRK -rearranged spindle-cell neoplasms. 73 Furthermore, in a series of nearly 500 soft-tissue tumors, pan-Trk positivity was found in multiple cases, yet only 1.0% of the tumors were confirmed NTRK fusion positive. 74 Another study describes three cases of cervical sarcomas harboring NTRK1 and NTRK3 fusions, each case exhibiting morphological overlap with uterine adenosarcomas. 75 However, none of the adenosarcoma controls showed comparable IHC or molecular comparisons.

While NTRK fusions are often known to be potent oncogenic drivers and therapeutic targets, particularly due to the success of Trk inhibitors, Ameline et al. 76 shed light on some of the complications of this. 76 From a patient cohort of 113, they identified three osteosarcomas with NTRK rearrangements, yet all were non-functional (lacking transcription, translation, or kinase domain preservation). This brings to light a significant caveat: just because an NTRK fusion is present, especially in more genomically rearranged and complicated sarcomas, it does not confirm the therapeutic vulnerability.

Taken together, these findings indicate that while IHC is profoundly useful as a screening tool, false positives are possible, underlining the imperative for molecular confirmation to avoid mistaking NTRK fusion phenocopies or wild-type expression for fusion-driven tumors.

Much of our discussion regarding Trk influence in sarcomas has so far revolved around NTRK gene fusions. As pervasive as they are, Trk’s role in oncogenesis is undoubtedly multifaceted. The Trk family members also function as direct effectors of oncogenic signaling through avenues. We now aim to discuss non-fusion mechanisms by which NTRK proteins contribute to tumor growth, survival, invasion, and therapeutic resistance across sarcoma types.

In a study by Kim et al., 77 researchers present a mechanistic hypothesis implicating TrkC as a driver of oncogenesis in Ewing sarcoma (ES) by acting as a stabilizer of the EWSR1 : FLI1 fusion protein. 77 This effect is non-canonical and operates through inhibition of proteasomal degradation when TrkC complexes with the EWSR1 : FLI1 complex. In effect, TrkC enhances tumor survival and metastasis and activates downstream PI3K/AKT targets. The role of TrkC in facilitating ES survival is multifaceted. (1) Proteins are stabilized, whereby TrkC directly binds to the fusion complex and inhibits its ubiquitination and proteasomal degradation. (2) TrkC blocks apoptosis and enhances cancer stem cell marker expression; in TrkC knockdown cells, there was increased caspase activation. (3) TrkC was also shown to suppress transforming growth factor-β signaling. In essence, TrkC’s role in ES makes it a targetable effector in fusion-driven sarcomas lacking the canonical NTRK presentation.

Another case of non-canonical, fusion-independent TrkC activity shows NTRK3 to be consistently overexpressed in BCOR/YWHAE -rearranged undifferentiated sarcomas. 78 Overexpression of wild-type TrkC at both the protein and mRNA level was observed and reinforced by positive pan-Trk IHC, but the mechanism of action is yet to be fully understood.

Building on the new lines of evidence that recognize Trk influence independently of fusion events, Lippai et al. 79 showed that in a cohort of 132 dedifferentiated sarcoma patients, nearly 28% of tumors had single NTRK gene amplifications, with no fusion events. Thirteen of the patient tumors had NTRK polysomy events. Previously, Lippai et al. 80 identified missense mutations (H604Y and G613V) in the tyrosine kinase domain of NTRK1 , concluding that these alterations upregulated downstream effects like PI3K/AKT signaling in addition to conferring Trk-inhibitor resistance.

The work and literature to date has been foundational to advancing the field of NTRK tumor biology, characterizing histological and immunophenotypic patterns of NTRK fusions and demonstrating the remarkable clinical responsiveness of Trk-inhibitor therapies. As the field advances, these insights offer an opportunity to refine our tumor classifications beyond fusion alone to include non-canonical Trk mechanisms, amplification, overexpression, and alternative splicing of Trk involvement. As we move forward with this lens, we may uncover vulnerabilities and shared signaling pathways across tumors that are not traditionally thought to engage in neurotrophin pathways.

Carcinomas

NTRK alterations in carcinomas are vast. The field has made great progress in identifying hundreds of NTRK fusion partners, especially in carcinomas with the highest incidence of fusions arising in thyroid carcinoma. 81 Given the aberrant nature of tumor biology, numerous mechanisms explain the changes in expression, upstream activation, and downstream influence of Trk receptors beyond fusion partnership.

Epigenetic modifications and non-coding RNA alter Trk expression levels

The most common influencers of changes in Trk expression include mutations, gene copy amplification, gene fusions, and mRNA overexpression. 28 Beyond this, there exist mechanisms responsible for modification in transcription and translation of NTRK genes, including methylation and non-coding RNAs.

NTRK gene promoters had a higher incidence of methylation in human colorectal cancer tissues, leading to suppressed mRNA expression of NTRK2 and NTRK3 and worse survival outcomes. 82 NTRK promoter methylation and its pro-oncogenic potential was highly dictated by disease context, where in some cases promoter methylation correlated with worse survival while others correlated with improved survival outcomes. 82 Moreover, using multi-omics analyses, a similar increase in methylation of NTRK genes in various carcinomas including lung adenocarcinoma, breast invasive carcinoma, and head and neck squamous cell carcinoma (HNSCC) was reported, correlating with decreased mRNA expression 81 following the pattern in colorectal cancer. Although these findings were reported with the purpose of discovering better prognostic biomarkers to predict clinical outcomes and characterize the NTRK genome, it would be valuable to investigate the mechanism behind this methylation to find out if it could be taken advantage of as a therapeutic dependency. Omics analyses is a promising tool to characterize NTRK influence across many disease types to help identify trends in disease-specific contexts.

Long non-coding RNAs (lncRNAs) are long transcripts that have little to no coding capacity but can regulate gene expression. Xing et al. 83 describe how the lncRNA sequence LINC01963 can alter chemosensitivity by modulating TrkB levels. MicroRNAs (miRNAs) conduct post-transcriptional regulation by binding mRNA and preventing their translation into protein. In the context of prostate cancer, inducing docetaxel resistance in prostate cancer cells leads to an overexpression of LINC01963. LINC01963 can bind to the miRNA miR-216b-5p, sequestering it away from NTRK2 mRNA, thereby increasing TrkB protein levels, and enhancing proliferation, migration, and invasion. This work 83 demonstrates lncRNA as a new type of candidate for therapeutic targeting and reveals an additional mechanism of Trk expression regulation in the context of cancer. However, it is unclear whether this mechanism is retained in different Trk-amplified cancer contexts, potentially identifying a reason for disease-specific variation. Exactly how these lncRNA levels are changing must be revealed in the context of NTRK post-transcriptional regulation.

Coordination with non-Trk receptors

At the protein level, Trk receptors undergo interactions that promote their downstream signaling. Typically, the Trk receptors undergo homodimerization after stimulation with their respective ligands. Tumor biology induces constitutive activation of the Trk receptors through mutations and fusions. In various cancers, these receptors can also undergo ligand-independent activation initiated by interaction with neighboring receptors. This dual-receptor coordination promotes more severe oncogenic phenotypes and resistance.

EGFR expression and resistance is often associated with NTRK biology. In HNSCC, TrkA promoted EGFR-inhibitor resistance, PNI, and metastasis by driving epithelial-to-mesenchymal transition (EMT) through STAT3 activation. 84 Like TrkA in HNSCC, TrkB correlated with EGFR resistance in esophageal squamous cell carcinoma, and investigation of downstream signaling pathways implicated MAPK/ERK signaling. 85 Independently, EGFR expression level correlates with sensitivity to the EGFR inhibitor afatanib, yet NTRK2 expression levels override this correlation, proving to be a stronger determinant of EGFR-inhibitor resistance. 85

Vaishnavi et al. 86 provide additional evidence for this Trk concerted biology with EGFR and demonstrate the potential of combinatorial treatment for the colluding receptors. Much like NTRK1/2/3 fusion-driven gliomas, 35 MEK1/2 and upstream EGFR inhibition in combination with TRK inhibition had a robust effect on TPR-NTRK1 -driven pancreatic, lung, and colorectal cancer models. This combination of inhibition prevented EGFR-mediated compensatory RAF/MEK/ERK activation and, therefore, the development of entrectinib resistance. 86 Moreover, the authors describe how BIM, a pro-apoptotic protein in the BCL2 family previously reported to be transcriptionally and post-translationally regulated by p -ERK, had an inverse relationship with entrectinib resistance via compensatory activation of EGFR along with HER2, MET, AXL, and EPH-A2. 86 Further work revealing the key players in this compensatory activation of overlapping signaling pathways would reveal additional combinations of therapies that mitigate the development of TRK-inhibitor resistance.

Nerve growth factor receptor (NGFR) also conspires with the Trks. Similarly to HNSCC, TrkA, in collaboration with NGFR, promoted PNI and aggressiveness of oral squamous cell carcinoma (OSCC). 87 Both receptors were differentially expressed in OSCC cases that were positive for PNI, metastasis to the neck, and cancer-induced pain. 87 Silencing of each independent receptor and in combination led to a decrease in proliferation and invasion in vitro . 87 Interestingly, only in vivo studies were able to demonstrate a more severe alteration in tumor growth, neck metastasis, and pain with combinatorial silencing of both TrkA and NGFR. 87 Additionally, TrkA and NGFR demonstrated control over different types of pain—thermal and mechanical pain, respectively. 87 Although yet to be confirmed via assay, differential gene expression implicated various pathways that require participation of the surrounding microenvironment including immune cell infiltration, EMT, and extracellular matrix crosslinking to promote PNI, metastasis, and pain. 87 These data demonstrate the vast reprogramming and influence TrkA can have on cancer cell behavior and their interaction with surrounding tissues. It is unclear whether there is true isoform specificity in the above study, given the impact that short hairpin RNA silencing can have on splice variants.

These works show a clear interaction between EGFR and NGFR with the Trk receptors. Beyond tracking Trk expression patterns, Wu et al. 88 revealed ligand-independent direct binding between TrkC and NGFR in triple-negative breast cancer, which contains high NGFR levels. 88 Through this activation, downstream signaling pathways MEK/ERK1 and PI3K/AKT activate the transcriptional machinery to promote the overexpression of NGFR. 88 Both NGFR and TrkC independently and synergistically promoted sphere formation, anoikis resistance, in vivo tumor growth, and in vivo metastasis. 88 Similarly, HER2-positive breast cancer has demonstrated an association between HER2 status with TrkA 89 and TrkB 37 expression. This demonstrates how different disease or amplification contexts may impact Trk expressional levels and signaling. Ligand-independent activity beyond fusion partnership to promote oncogenic activity requires more investigation.

The receptor collaborations reported above promote more aggressive disease and complicate therapeutic sensitivities. Clarifying exactly how these receptors interact would reveal interesting candidates for therapeutic targeting and potential combinatorial therapies.

Trk-mediated interplay between the tumor and the surrounding microenvironment

As discussed, Trk receptors transform cancerous cells, promoting a more stem-like phenotype. This phenotype is characterized by an increase in metastasis, invasiveness, PNI, and levels of N-cadherin, fibronectin, transcription factors Twist and Snail, STAT3 activation, and Wnt signaling. Recent works elucidate how this Trk-mediated transformation is interlaced with the influence of tumor cells on their surrounding microenvironment and vice versa.

Jiang et al. 90 provide strong evidence of how much impact surrounding stromal cells within the tumor microenvironment can have on cancer progression. A co-culture system with pancreatic stellate cells (PSCs) and pancreatic cancer cells demonstrates high secretion levels of NGF from PSCs and, therefore, high expression levels of TrkA in adjacent pancreatic cancer cells. 90 The presence of PSCs transformed the pancreatic cancer cells to be more proliferative and invasive via PI3K/AKT/GSK-initiated EMT. 90 The role of the TrkA/PI3K/AKT axis in maintaining the survival of neural progenitors is hijacked to push mesenchymal phenotypes. In parallel, increased TrkA expression in HNSCC contributed to worse clinical outcomes including increased PNI and metastasis. 84 Knockdown of TrkA decreased the aggressiveness of HNSCC cells in vitro , decreasing proliferation, colony formation, migration, invasion, and tumor growth in vivo . 84 The authors posited that elevated TrkA expression in HNSCC cells and elevated NGF secretion in neural cells eludes to a potential chemoattractant for cancer-nerve cell communication, 84 but further experimentation is required to validate this hypothesis.

Acetylcholine (ACh) from both epithelial Dclk1 tuft cells and cholinergic nerves has been found to drive gastric tumorigenesis through a biphasic mechanism. In early carcinogenesis, tuft cells are the main source of ACh, whereas in advanced tumorigenesis, the production of ACh shifts to expanding cholinergic nerve fibers (axonogenesis). 91 ACh acts on muscarinic acetylcholine receptor 3 (M3R) on gastric epithelial cells, activating Gq/11 signaling, thereby stimulating NGF expression within the epithelium. 91 NGF bound TrkA receptors found on stromal nerves and further prompted cholinergic innervation, consequently creating a positive feedback loop that sustains high ACh levels within the tumor microenvironment. 91

Researchers found that the epithelial overexpression of NGF in vivo was sufficient to induce metaplasia, dysplasia, and adenocarcinoma, as well as accelerate chemically induced tumorigenesis; these effects were abrogated by M3R deletion. 91 Inhibition of TrkA disrupted NGF-driven cholinergic innervation, suppressed epithelial proliferation, and blocked growth of the tumor; however, nerve growth and proliferation were rescued upon inhibitor withdrawal, which indicated dependence on NGF. 91 Downstream, M3R was able to activate signaling of Yes-associated protein (YAP), a β-catenin transcriptional co-activator, thereby enabling robust activation of Wnt target genes, given Apc tumor-suppressor gene loss. 91 The loss of M3R prevented YAP activation despite β-catenin nuclear localization, revealing an uncoupling of the Wnt pathway’s transcriptional output from upstream stabilization. 91

In human gastric cancer, NGF expression is represented among ~53%–64% of human gastric cancer samples and is significantly correlated with YAP activation, advanced stage, and metastasis. 91 This exciting work advanced the field’s understanding of mechanisms and implications of Trk-mediated increases in tumoral innervation and how it produces more advanced disease. Moreover, these findings clarify an ACh/M3R/NGF/TrkA/YAP axis as a key neural-epithelial signaling mechanism in gastric cancer, defining multiple intervention points (ACh release, M3R activation, NGF/TrkA response, and YAP activity) that have therapeutic potential.

One study by Renz et al. identifies the role of neuropsychological stress in accelerating pancreatic ductal adenocarcinoma (PDAC) development through a β2-adrenergic feedforward loop. In PDAC, neural density, hypertrophy, and norepinephrine (NE) levels are elevated compared to healthy pancreatic levels, therefore indicating tumor-driven axonogenesis and sustained adrenergic signaling. 92 Oncogenic Kras mutant epithelial cells responded to systemic catecholamines released during chronic stress by upregulating and activating β2-adrenergic receptors (ADRB2), which translocate from cytoplasmic to membranous localization. 92 ADRB2 signaling engaged PKA and ERK pathways to accelerate acinar-to-ductal metaplasia, proliferation, and secretion of neurotrophins: NGF in murine PDAC and mainly BDNF in human PDAC. 92 These neurotrophins act through TrkA receptors and TrkB receptors to promote axonogenesis and NE delivery within the tumor. 92 In mouse models, blocking ADRB2, inhibiting Trk, and treating with gemcitabine prolonged survival. 92 In patients with resected PDAC, non-selective β-blocker implementation correlated with reduced nerve density, lower levels of BDNF, and improved survival. 92 Taken together, these findings reveal key mechanistic insights in which adrenergic signaling influences innervation pathways to apply tumor-promoting neurotransmitter production, highlighting β2-adrenergic and Trk pathways as dual therapeutic targets in PDAC. Beyond this, the secretion of psychologically related factors promoting Trk tumorigenesis highlights how neurological signaling mechanisms can be seized by the tumor via Trk signaling.

Besides factors secreted by neighboring cells, immune cells can promote oncogenicity via Trk and therefore promote EMT. For example, a protumoral and antitumoral immune response can be developed against cancer-associated Trk receptors. 93 This was demonstrated by anti-TrkB antibodies isolated from breast cancer patients with both agonistic and antagonistic effects in vitro and in vivo . 93 The agonistic TrkB antibody generated by these patients promoted tumor growth and was able to initiate canonical downstream signaling including CRE, NFAT, ERK, PLCγ, and AKT pathways. 93 In contrast, the antagonistic TrkB antibody diminished tumor growth and elicited epithelial morphological changes in mesenchymal-to-epithelial transition. 93 TrkB was successfully utilized as a target for immunotherapy for multiple breast cancer cell lines. 94 The reason for this success is the cancer-specific mutant of TrkB identified due to its immunogenicity in breast cancer patients. 94 This is an exciting new avenue for therapeutic potential associated with Trk receptor immunity.

In hepatocellular carcinoma, TrkC activated EMT by stabilizing the PTEN-negative regulator and STAT3 activator, DJ-1, consequently inducing stemness traits and chemoresistance. 95 TrkC formed a complex with DJ-1 after kinase activation and phosphorylated STAT3. 95 The DJ-1-TrkC complex’s initiation of STAT3 activity led to downstream increases in expression of embryonic or cancer stemness markers and EMT transcription factors. 95 In addition, NT-3 was a regulatory force behind cancer stem cell generation in NSCLC and impacted their tumor-initiating qualities. 96 NT-3 promoted cancer stem cell generation, upregulated stemness transcription factors, decreased chemosensitivity, and advanced tumorigenicity in vivo . 96 The authors argued that NT-3/TrkC-initiated Wnt signaling is the pathway behind the increase in expression of stemness markers. 96 This highlights how Trk biology can promote stemness properties, implicating Trks to modulate the regulatory capacity of cancer stem cells.

Trk receptor utilization in tumor cells consistently pushes for stemness properties and maintains stem-like cells across many tumor types. Cancer stem cells are capable of both initiating tumors and promoting their long-term maintenance and recurrence through their ability to engage self-renewal and differentiation. They can also shape the tumor microenvironment by maintaining dialog with adjacent cells via secreted factors like neurotrophins. This Trk-mediated crosstalk promotes a protumoral environment and implicates Trk signaling in neural pathways observed to induce invasive tumor patterns such as innervation and PNI.

Melanoma

Melanomas have also demonstrated morphological changes that align with EMT. Mouse melanocytes transduced to express NTRK3 fusions ETV6 : NTRK3 and MYO5A : NTRK3 promoted stark differences in cell morphology despite activating similar downstream pathways, ERK and AKT. 97 NTRK3 fusion binding partner ETV6 promoted a nuclear localization of the fusion protein and rounded, flat morphology whereas binding partner MYO5A promoted a dendritic localization and morphology. 97 Such morphological changes could be indicative of EMT influence but must be validated. This variation in localization is highly critical to the subsequent activation and activity of the Trk receptors. Zhu et al. 98 describe a change in Trk distribution with the loss of the N terminus due to the gain of a fusion partner. The typical membranous localization of the full-length receptor is lost, and liquid-liquid phase separation sites appear as puncta in the cytoplasm or net-like distribution associated with the endoplasmic reticulum. 98 These areas act as hubs for downstream hyperactivation, engaging local proteins involved in niches of signaling. 98 Like in the case of fusion containing mouse melanocytes, the fusion partner dictates the type of localization, and understanding how this localization induces changes in activity is imperative.

HEMATOLOGIC CANCERS

While Trk receptor influence is well studied in solid tumors, the spectrum of NTRK -driven oncogenic alterations is increasing in other landscapes, such as in hematologic cancers.

In this section, we aim to discuss emerging data that implicates NTRK1 , NTRK2 , and NTRK3 in a wide range of cancer-driving roles in myeloid and lymphoid malignancies such as acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), and other myeloproliferative neoplasms. We present a critical analysis of how Trk signaling disrupts intracellular dynamics, examining Trk-driven interactions through a broader mechanistic lens that includes conformational dysregulation, altered signaling, and disruption of normal hematopoietic developmental timelines. We explore how Trk receptors may act as drivers within hematologic cancers and how this understanding may generate therapeutic vulnerabilities yet to be fully exploited by current clinical approaches.

Interestingly, 5% of patients presenting with diverse hematologic neoplasms harbor NTRK2 or NTRK3 point mutations. 99 Accordingly, the researchers offered a rare molecular lens into Trk-driven leukemias by using molecular dynamics simulations to study four cancer-causing mutations identified in patients diagnosed with myelofibrosis, chronic and atypical leukemia, and T-ALL. These mutations (TrkB A203T and R458G, and TrkC E176D and L449F) occurred in the extracellular, transmembrane, and juxtamembrane domains of the receptor. Certain mutations conferred oncogenic capabilities upon transformed cells. For example, A203T increased TrkB flexibility and destabilized its structure, whereas R458G rigidified the protein, potentially changing receptor dimerization or downstream interactions. Both TrkC mutations lowered its flexibility and solvent accessibility, suggesting that these mutations caused the protein to be more compact. These findings highlight that point mutations, though less prevalent than fusions, can meaningfully disrupt Trk structure, dynamics, and downstream interactions in blood cancer contexts. Future directions might consider exploring how these conformational mutations alter ligand binding, activation state, or intracellular signaling.

In parallel, deep sequencing was performed on 185 patients with AML, ALL, and myeloproliferative neoplasms and found point mutations in NTRK2 or NTRK3 in ten patients, revealing nine unique variants. Four of the nine mutations were shown to be oncogenic by functional assays ( NTRK2R458G , NTRK2A203T , NTRK3E176D , and NTRK3L449F ). 100 Three of these mutations were in the extracellular or transmembrane domain and conferred enhanced receptor dimerization and surface localization, which amplified downstream activation. The fourth mutation was found in the juxtamembrane domain and participated in TrkB activation through interactions with membrane lipids. All four mutations were sensitive to entrectinib.

CML is mostly characterized by the BCR-ABL rearrangement, occurring on chromosomes 22 and 9, resulting in the formation of the disease-causing Philadelphia chromosome. This fusion can also drive ALL and AML, but to a lesser extent than in CML. This abnormal gene results in the constitutive activation of tyrosine kinase BCR-ABL and is targeted with tyrosine kinase inhibitors, such as imatinib. However, as many patients develop resistance to imatinib due to point mutations in the BCR-ABL gene, Zhang et al. 101 are investigating the role of epigenetic dysregulation in the pathogenesis of hematologic cancer. They found that some histone lysine demethylases (KDMs), such as KDM6A, are notably upregulated in adult CML, and KDM6A has been shown to have point mutations in B cell ALL (B-ALL) and T-ALL. 101 The mechanism by which KDM6A confers protection to CML cells from imatinib is non-canonical and instead relies on a TrkA-mediated mechanism. 101 KDM6A functions as a transcriptional activator of NTRK1 , driving its upregulation. Researchers showed that KDM6A relies on the YY-1 transcription factor to promote transcriptional activation of the NTRK1 gene, resulting in NGF signaling and, consequently, imatinib resistance in CML. 101 Therefore, a new mechanistic understanding of CML resistance to imatinib identifies NTRK1 transcription as a driver of imatinib resistance and positions KDM6A as a potentially druggable target in hematologic cancers.

Spotlighting on TrkB signaling, BDNF is shown to be a critical survival factor in B cell chronic lymphocytic leukemia (B-CLL). 102 BDNF contributed to the nurse-like secretome, promoting leukemic cell survival by turning on the NTSR2-TrkB receptor complex, which was overexpressed in B-CLL cells. Activation of the NTSR2-TrkB complex led to Src kinase activation and upregulation of anti-apoptotic proteins, such as Bcl-2. Inhibition of BDNF increased apoptosis. These findings position the BDNF/TrkB signaling axis as a promising avenue for future research and therapeutic approaches in dismantling tumor-supporting microenvironments.

Similar work establishes a functional link between the BDNF/TrkB axis and the extracellular vesicle (sEV)-mediated immunotherapy resistance in diffuse large B cell lymphoma. 103 Researchers found that TrkB activation enhances the production of sEVs and CD20 within those vesicles. CD20 is a surface protein on B cells and is the target of rituximab (Rtx). Decreased CD20 expression is a key mediator of Rtx resistance. In this context, TrkB signaling is linked to immunotherapy resistance via CD20 vesicle trafficking.

Recent large-scale sequencing efforts revealed the relevance of NTRK1 fusions in hematologic malignancies. 104 In an analysis of 742 multiple myeloma patients, researchers found three NTRK1 fusions ( TPM3 : NTRK1 , TPR : NTRK1 , and ARHGEF2 : NTRK1 ) with intact kinase domains and high transcriptional expression. The researchers concluded that the three patients with NTRK1 fusions were eligible for targeted therapies.

The current literature suggests that NTRK signaling is a key contributor to the pathogenesis of various hematologic malignancies through point mutations, fusion events, receptor ligands, and overexpression. Despite emerging evidence, NTRK research within hematologic cancers remains an underexplored domain, representing significant opportunities for mechanistic and therapeutic discovery.

THERAPEUTIC IMPLICATIONS

Trk-targeted therapies have emerged as novel and highly effective treatment strategies for patients with Trk fusion-driven malignancies ( Table 2 ).

In 2012, GNF-5837 was identified as a promising Trk inhibitor through screening and optimization of oxindole-based compounds, demonstrating potent antiproliferative activity in Trk-expressing cells and tumor regression in mouse models; however, it does not effectively cross the blood-brain barrier, limiting its potential for CNS applications. 105 The study also disclosed the first crystal structure of TrkC with a TrkC inhibitor, which was a catalyst for development of other selective Trk inhibitors, paving the way for the design of next-generation compounds with improved specificity and pharmacokinetic profiles. 105 GNF-5837 has also been shown to suppress tumor growth, survival, and migration in renal cell carcinoma by inducing cell-cycle arrest and apoptosis through inhibition of TrkA and TrkB downstream signaling. 106

The main targeted Trk therapies, larotrectinib (LOXO-101) and entrectinib (RXDX-101), have been pivotal in advancing treatment options for Trk-driven malignancies. Larotrectinib is a highly selective, orally available, and a potent pan-Trk inhibitor that has demonstrated promise in treating a broad range of malignancies across adult and pediatric patients, with limited adverse events reported in clinical trials and improvements in health-related quality of life. 107 – 114 Entrectinib, a potent inhibitor of ALK, ROS1, and Trk with blood-brain barrier permeability, has demonstrated significant efficacy in treating tumors with relevant gene fusions, including CNS and extracranial tumors, with most adverse events reported as mild to moderate, supporting its potential as a safe and effective treatment option. 115 – 117

While larotrectinib and entrectinib have significantly advanced the treatment of Trk-driven malignancies, the emergence of resistance mechanisms remains a critical challenge. These resistance mechanisms can be broadly categorized into on-target resistance, which involves mutations within the kinase domain of the NTRK gene itself; and off-target resistance, which involves the activation of other signaling pathways that bypass the inhibited Trk protein, therefore allowing cancer cells to continue to survive. 114 For on-target resistance mechanisms, the three principal regions where these mutations occur are the solvent front, gatekeeper residue, and xDFG motif, where mutations lead to amino acid substitutions that sterically interfere with the binding capacity of the inhibitor. 114 Activation of the MAPK pathway and insulin-like growth factor receptor type 1 (IGF1R), along with mutations, rearrangements, or amplifications in EGFR, KRAS, and BRAF, are well-documented off-target resistance mechanisms that bypass the kinase domain. 114 Notably, the G595R solvent front mutation and the G667C xDFG mutation have been specifically implicated in resistance to entrectinib. 118

Repotrectinib (TPX-0005), a compact macrocyclic next-generation multikinase inhibitor, was designed to address resistance mechanisms in mutated ALK, ROS1, and Trk kinases, particularly those with solvent-front mutations. 119 Its structure allows it to overcome steric hindrance at the ATP-binding site, enabling superior efficacy while exhibiting favorable CNS penetration properties. 120 Beyond Trk inhibition, repotrectinib also targets FAK, JAK2, and SRC signaling, which are involved in resistance pathways such as target gene amplification, bypass signaling, EMT, and metastasis. 119 Additionally, repotrectinib has demonstrated greater potency against wild-type TrkA/B/C mutations compared to larotrectinib and entrectinib, highlighting its potential as a robust therapeutic option. 121

The TRIDENT-1 trial represents a pivotal study evaluating the efficacy and safety of repotrectinib in patients with advanced solid tumors harboring ROS1 or NTRK gene fusions, including those with resistance mutations. While efficacy results from the TRIDENT-1 trial are primarily focused on ROS1-positive cohorts, the safety population also included patients with NTRK fusion-positive solid tumors, offering valuable insights into repotrectinib’s safety profile. The most common treatment-related adverse events were dizziness (58%), dysgeusia (50%), and paresthesia (30%), which were predominantly low-grade and manageable through dose modifications or interruptions and with only 3% of patients discontinuing treatment due to adverse events, highlighting the tolerability of repotrectinib. 122 Although limited efficacy data on Trk fusions were available from this trial, the inclusion of NTRK fusion-positive patients in the safety analysis highlights the potential applicability of repotrectinib across a range of NTRK fusion-driven cancers.

Selitrectinib (LOXO-195) is a highly potent and selective next-generation TRK kinase inhibitor that is structurally designed to overcome solvent-front resistance mutations such as G595R in TrkA and G623R in TrkC by accommodating the bulky, positively charged arginine side chain without steric clashes. 123 Preclinical studies have revealed selitrectinib’s ability to suppress phospho-TrkA and inhibit tumor growth in TrkA-dependent models, including ΔTrkA-G595R and TPM3 : NTRK1 fusion-positive colorectal cancer. 123 In clinical cases, selitrectinib has shown therapeutic promise in patients with acquired resistance to first-generation Trk inhibitors, with limited adverse events. 123 , 124

Lestaurtinib (CEP-701), a neurotrophin-receptor-linked tyrosine kinase inhibitor, showed limited tolerability at doses above 40 mg twice daily due to gastrointestinal toxicities and lack of objective tumor response in clinical trials in the early 2000s, whereas its derivative CEP-2563 demonstrated improved solubility, manageable toxicities, and promising preclinical antitumor activity, highlighting its potential for further development. 125 , 126 In a phase 1 clinical trial assessing lestaurtinib for pediatric neuroblastoma, the drug aimed to target TrkB but did not demonstrate sustained inhibition of TrkB phosphorylation. 127 Adverse events included liver function test abnormalities in 33% of patients, transaminase elevation in 64%, pancreatitis in three cases, and two second malignancies, with 42 patients discontinuing the trial due to progressive disease, toxicity, or withdrawal of consent. 127

Pegcantratinib, a potent topical TRK inhibitor, has shown promise in treating disfiguring CYLD cutaneous syndrome (CCS) tumors by targeting overexpressed Trk pathways, offering localized efficacy while minimizing systemic side effects and improving patient outcomes through reduced tumor symptoms and enhanced quality of life. 128 , 129 Lestaurtinib has also shown reduced colony formation and proliferation in 3D cultures of CYLD mutant tumor. 130

Merestinib (LY2801653) is a type II NTRK kinase inhibitor that demonstrates superior potential compared to type I inhibitors like entrectinib and larotrectinib, due to its unique binding mechanism to the DFG-out configuration of the kinase. 118 In vitro , merestinib effectively inhibits NTRK1 phosphorylation, including in cells with TPM3 : NTRK1 fusions, while also suppressing downstream pathways like ERK and MKNK1/2, resulting in reduced cell proliferation and anchorage-independent growth. 118 In vivo- , merestinib significantly reduced tumor growth in TPM3 : NTRK1 and ETV6 : NTRK3 fusion models and led to tumor regression in patient-derived xenograft models. 118 Merestinib retains activity against acquired resistance mutations, such as G667C, that reduce the efficacy of type I inhibitors, while its inhibition of MKNK1/2-mediated phosphorylation of eIF4E offers a dual-action mechanism, distinguishing it from other NTRK inhibitors. 118 These findings position merestinib as a promising therapeutic option for NTRK fusion-driven tumors, including those with resistance to existing treatments.

Zurletrectinib is a next-generation TRK inhibitor demonstrating strong preclinical efficacy against NTRK fusion-positive tumors, including those resistant to first-generation Trk inhibitors. 131 It exhibits superior potency against TrkA G667C and TrkC G696C mutations, enhanced brain penetration, and improved survival in Trk-mutant glioma models compared to selitrectinib and repotrectinib, with ongoing clinical trials demonstrating promising response and disease control rates, including in patients with brain metastases. 131

Combination therapies have shown significant promise in overcoming resistance mutations by targeting multiple pathways simultaneously, reducing the likelihood of tumor escape mechanisms. 123 , 132 , 133 By addressing both primary and compensatory signaling pathways, these strategies can enhance efficacy and durability of response compared to monotherapy. In the context of NTRK fusion-positive tumors, combining Trk inhibitors with agents targeting downstream or parallel pathways may mitigate the impact of resistance mutations. This approach should be further explored in future studies to optimize treatment outcomes and expand therapeutic options for patients with advanced or refractory cancers.

The promise of new and innovative therapies offers exciting potential to overcome the limitations of current treatment strategies for Trk-driven cancers. GNF-5837-loaded albumin hybrid nanoparticles (GNF-Alb-HNPs) represent a novel therapeutic approach, demonstrating enhanced TrkA inhibition, sustained drug release, and superior antiproliferative, pro-apoptotic, and antimetastatic effects compared to the free drug in breast cancer cell models. 134 TrkB-targeted chimeric antigen receptor (CAR) T cell therapy, leveraging BDNF and NT4 ligands, has also shown promise in effectively targeting TrkB-overexpressing solid tumors and cancer stem-like cells, with NT4-CAR T cells demonstrating superior tumor growth inhibition in preclinical hepatocellular carcinoma models. 135 Emerging approaches are not only addressing resistance mechanisms but also expanding therapeutic possibilities through advanced drug delivery systems.

Many next-generation Trk inhibitors lack extensive clinical data, highlighting a critical gap in their development and evaluation. Additionally, there is a significant lack of research and testing within pediatric populations, leaving an underserved demographic with limited therapeutic options. Addressing these gaps is imperative to ensure that these innovative treatments are accessible and effective across all age groups, paving the way for broader clinical applicability and improved outcomes.

CONCLUDING REMARKS

NTRK s 1 , 2 , and 3 and their receptors TrkA, TrkB, and TrkC, respectively, drive a myriad of developmental processes that, when perturbed, can promote oncogenicity. The literature demonstrates that changes in Trk expression, such as increases in gene copy number, splice variants, or mutations resulting in NTRK fusions, drive malignancy across cancer. Given that Trk receptors can modulate the expression of MYC, EGFR, PDGFR, and HER2, as well as pathways canonically associated with oncogenesis such as the RAS/MEK/ERK or PI3K/AKT pathways, it is paramount to understand the mechanisms by which aberrant Trk activity drives malignancy.

Studies show several mechanisms used by Trk receptors to promote tumorigenesis, the most common being genetic mutations and fusions. These changes dictate intracellular localization of Trks, exposing them to a variety of signaling niches that can alter their downstream signaling capabilities. Trk expression is also promoted by increases in neurotrophins secreted by adjacent cells, which can confer nerve infiltration properties and aid in the establishment of cancer-neural synapses. Furthermore, by hijacking Trk’s role in development to promote stemness and EMT, cancer stem cells can become more aggressive and resistant to therapies.

Current pan-Trk inhibitors allow for concerted targeting of shared mechanisms between TrkA, TrkB, and TrkC. However, for optimized treatment, it is imperative to explore the mechanistic underpinnings of individual Trk receptors. Given the advancement of various research tools such as predictive cell models for NTRK fusion response outcomes, multi-omics analyses, and methods to distinguish specific splice variant roles, it is now more feasible to delineate overlapping mechanisms between each Trk receptor. Moreover, combinatorial therapy aimed to study these complex biological maps of aberrant Trk activity will help mitigate off-target effects for the next generation of Trk modulators.

As we enter this new wave of technological advancement, interdisciplinary insights from cancer biology, immunology, and neuroscience will be paramount to our evolving understanding of Trk-mediated pathways in cancer. Overall, this field of study has only scratched the surface, setting the stage for new discoveries in Trk biology across multiple scientific domains.

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health/National Cancer Institute, grant no. K22CA258953 (to S.S.P.).

Footnotes

DECLARATION OF INTERESTS

The authors have no competing interests to declare.

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