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Review

NTRK Therapy among Different Types of Cancers, Review and Future Perspectives

by
Nyein Wint Yee Theik
1,
Meri Muminovic
2,
Andres M. Alvarez-Pinzon
3,*,
Ahmed Shoreibah
1,
Atif M. Hussein
4 and
Luis E. Raez
4,*
1
Division of Internal Medicine, Memorial Healthcare System, Pembroke Pines, FL 33028, USA
2
Memorial Cancer Institute, Memorial Healthcare System, Pembroke Pines, FL 33028, USA
3
Memorial Cancer Institute, Office of Human Research, Florida Atlantic University (FAU), Pembroke Pines, FL 33028, USA
4
Memorial Cancer Institute, Memorial Healthcare System, Florida Atlantic University (FAU), Pembroke Pines, FL 33028, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(4), 2366; https://doi.org/10.3390/ijms25042366
Submission received: 3 January 2024 / Revised: 5 February 2024 / Accepted: 7 February 2024 / Published: 17 February 2024
(This article belongs to the Section Molecular Oncology)
Browse Figure
Review Reports Versions Notes

Abstract

:
Neurotrophic tyrosine receptor kinase (NTRK) has been a remarkable therapeutic target for treating different malignancies, playing an essential role in oncogenic signaling pathways. Groundbreaking trials like NAVIGATE led to the approval of NTRK inhibitors by the Food and Drug Administration (FDA) to treat different malignancies, significantly impacting current oncology treatment. Accurate detection of NTRK gene fusion becomes very important for possible targeted therapy. Various methods to detect NTRK gene fusion have been applied widely based on sensitivity, specificity, and accessibility. The utility of different tests in clinical practice is discussed in this study by providing insights into their effectiveness in targeting patients who may benefit from therapy. Widespread use of NTRK inhibitors in different malignancies could remain limited due to resistance mechanisms that cause challenges to medication efficacy in addition to common side effects of the medications. This review provides a succinct overview of the application of NTRK inhibitors in various types of cancer by emphasizing the critical clinical significance of NTRK fusion gene detection. The discussion also provides a solid foundation for understanding the current challenges and potential changes for improving the efficacy of NTRK inhibitor therapy to treat different malignancies.

1. Introduction and Epidemiology

Neurotrophic tyrosine receptor kinase (NTRK) inhibitors for certain tumors expressing these fusion proteins have recently become a new favored treatment [1]. The NTRK genes, including NTRK 1, 2, and 3, encode tropomyosin receptor kinase (TRK) receptor family proteins like TRKA, TRKB, and TRKC, known as TRK, responsible for neural cell progress and activities [2]. Any variations or rearrangements of the genes could lead to the activation of neural cells [3]. Among the NTRK genes, NTRK1 was initially recognized as an actionable oncogene in colon cancer by Mariano Barbacid and colleagues in 1982 [4]. Different NTRK translocations or gene fusions and TRK protein overexpression forms were eventually observed in solid tumors besides colon cancer, including other gastrointestinal, gynecological, thyroid, lung, and pediatric malignancies [5].
Among a total of 55 patients in phase 2 of the NAVIGATE trial, 55% of individuals remained progression-free after one year of follow-up, which demonstrated an excellent overall response rate (ORR) to larotrectinib (75% with a 95% confidence interval [CI] of 61–85%) [6]. This groundbreaking trial led to a first-generation NTRK inhibitor (larotrectinib) being approved by the Food and Drug Administration (FDA) that is histology agnostic, including treatment for adult and child malignancies. After that, another first-generation inhibitor (entrectinib) became the second inhibitor approved by the FDA [7].
According to the phase-2 NAVIGATE trial and phase-1 LOXO-TRK-14001 trial, first-generation NTRK inhibitors were found to have a rapid response with effectiveness and survival benefit for the patients with a two-year progression-free survival (PFS) of 67% (95% CI 44–90%) [6]. Therefore, recognizing NTRK gene fusions in various solid tumors is crucial for future cancer management, potentially extending the survival of affected patients.

2. Different Methods for NTRK Gene Fusion Detection

Diverse methods exist for detecting aberrant NTRK gene fusions. Each test has its characteristics, limitations, and benefits; however, the choice of test is typically determined by sample diversity and the test’s sensitivity and specificity. One molecular cytogenetics technique called fluorescence in situ hybridization (FISH) employs fluorescently labeled deoxyribonucleic acid (DNA) probes to detect abnormal rearrangements in fusion genes. Formalin-fixed, paraffin-embedded (FFPE) tumor specimens are typically used to visualize aberrant fusion genes. FISH is frequently used to diagnose certain cancers, such as secretory breast carcinoma (SBC) and infantile fibrosarcoma, due to the prevalence of NTRK genes in these conditions [8].
Reverse transcriptase polymerase chain reaction (RT-PCR) is generally helpful in detecting NTRK fusions by amplifying ribonucleic acid (RNA) molecules and is applied as a confirmation test after other tests show positive results for abnormal expression [9]. One of the most frequently used tests, Next-Generation Sequencing (NGS), is based on known NTRK fusion partners, validating the identification of fusion events. The benefit of the test is that it warrants comprehensive genomic profiling and can detect other actionable genetic alterations in addition to NTRK fusions and their various variants. Additionally, NGS is commonly used for comprehensive genomic profiling that includes these genes [10].
Immunohistochemistry (IHC) is one of the most widely used and accessible assays due to its low cost and ability to detect abnormal NTRK protein expressions. The specificity and sensitivity are usually gene partner-dependent and tumor-dependent, making it an excellent screening test overall. However, confirmation tests are occasionally advised because its value is limited to screening [11]. Total transcriptome RNA sequencing necessitates sequencing the entire RNA transcriptome, which enables the identification of aberrant fusion events based on significant alignment patterns and breakpoints, even though it is pricey and laborious, and RNA technology is less commonly used than DNA NGS.
In summary, DNA NGS in tissue is the best technology to detect NTRK fusions, and RNA NGS is the best complement to identify these fusions. Liquid biopsies are an alternative to DNA NGS; however, RNA NGS is not yet widely available in liquid biopsies.

3. TRK Biology and Ontogenesis

NTRK belongs to the tyrosine receptor kinase family, which includes NTRK1, NTRK2, and NTRK3, encoding for TRKA, TRKB, and TRKC, respectively. NTRK1 was initially identified as an oncogene in 1982 by Mariano Barbacid and colleagues during gene transfer assays aimed at discovering genes with transforming capabilities in human tumor specimens, specifically those from colon cancer [4]. Subsequently, the cDNA of the NTRK1 proto-oncogene was isolated and characterized as TRKA, a 790-amino acid protein displaying features characteristic of cell surface receptor tyrosine kinases, in 1989 [12]. TRKA was found to be expressed in the nervous system in 1991 and recognized as a receptor for neurotrophic nerve growth factor (NGF) [13]. Additionally, TRKB and TRKC were considered members of the same family of receptors, and all TRK receptors and NTRKs play a vital role in nervous system development, differentiation, and apoptosis.
TRK receptors are capable of binding to different ligands such as NGF for TRKA, brain-derived neurotrophic factor (BDNF) or neurotrophin 4 (NT-4) for TRKB, and neurotrophin 3 (NT-3) for TRKC [14]. Neurotrophins were initially identified as survival molecules for neurons. The binding of neurotrophins to their alternative receptor, p75NTR, primarily results in the activation of JNK signaling cascades, as well as the P75NTR-interacting protein (NRAGE, also known as melanoma-associated antigen D1), and P75NTR-associated cell death executor (NADE) adaptors that promote cell cycle arrest and apoptosis directly [15,16,17].
Valent et al. first mapped NTRK1, NTRK2, and NTRK3 to human chromosomes 1q22, 9q22, and 15q25 by fluorescence in situ hybridization in 1997 [18]. In 2012, key regions for achieving selective inhibition were recognized from TRKA and TRKB crystal structures [19]. Although NTRK was identified as an oncogene in 1982, the actual development of NTRK inhibitors began in 2015. The overall timeline of NTRK genes and inhibitor therapy is summarized in Table 1.
TRK receptors can be activated by different mechanisms, such as the G-protein coupled receptor (GPCR) mechanism, without neurotrophins’ involvement. In order to increase the survival of neural cells through AKT activity, the TRK receptor can be activated by two GPCR ligands, adenosine, and pituitary adenylate cyclase-activating polypeptide (PACAP) [20]. Somatic NTRK mutation has been identified in various tumor types, including colorectal and lung cancers such as large cell neuroendocrine carcinoma and NSCLC, as well as melanoma and acute myeloid leukemia [21,22,23,24].

4. Mechanisms of Action

Both first-generation NTRK inhibitors are orally administered and warranted to treat adult solid malignancies and some pediatric tumors. They bind selectively to the ATP-binding site of abnormal NTRK gene fusion proteins, inhibit ATP from binding to the fusion protein, and inhibit the action of signals in its downward path that collaborate in the growth of cells, survival, and differentiation. This inhibition disrupts the disruption of abnormal signaling cascades and encourages tumor regression (Figure 1) [25].
Correspondingly, both first-generation inhibitors, entrectinib and larotrectinib, are highly effective in inhibiting the growth of BaF3 cells transduced with different NTRK fusions and of primary cancer cell lines harboring NTRK rearrangements in vitro and in mice via inhibition of MAPK, PI3K-AKT, PKC, and STAT3 pathways [26]. NTRK inhibitors have shown various advantages for patients with tyrosine kinase tumors, with practical and long-lasting responses approved for adult and pediatric populations [27].

5. First-Generation NTRK Inhibitors

5.1. Larotrectinib

First-generation NTRK inhibitor trials predominantly adopt a basket trial design due to the infrequent occurrence of NTRK fusions within specific tumor types. Larotrectinib, the inaugural pan-TRK inhibitor, selectively targets TRK receptor proteins, namely TRKA, TRKB, and TRKC. Three pivotal clinical trials, namely LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431), collectively enrolled 55 eligible patients across 21 distinct cancer types [6,28,29]. The cohort comprised both adult and pediatric patients administered with 100 mg of larotrectinib twice daily. The objective response rate (ORR) was calculated at 75% (with a 95% confidence interval of 67–85%) [6]. Notable adverse effects, such as gastrointestinal and central nervous system manifestations like dizziness, were observed; however, the majority were graded as mild (Grade 1) and manageable. An updated analysis conducted in 2021, encompassing a total of 218 samples, reported an ORR of 75%, comprising a complete response (CR) rate of 22%, a partial response (PR) rate of 53%, stable disease (SD) in 16% of cases, and progressive disease (PD) in 6%. Larotrectinib received approval for the treatment of NTRK gene fusion tumors in both adult and pediatric populations in November 2018. Notably, most treatment-related adverse events were categorized as Grade 1–2, with only 18% exhibiting Grade 3–4 severity in subsequent investigations [30]. Grade 3 events included myalgia, hypersensitivity reactions, and weight gain, with only 2% of patients requiring discontinuation of larotrectinib due to side effects, thus underscoring its favorable safety profile as a therapeutic option.

5.2. Entrectinib

Entrectinib is a multikinase inhibitor that halts reactive oxygen species (ROS) oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) in addition to blocking tyrosine receptor kinase A, B, and C [31]. Integrated analysis of four trials in 2019 included STARTRK-1, STARTRK-2, and ALKA-372-001, with 54 adult patients aged over 18 years who received entrectinib [32]. Common toxicities are noted in Grades 1 and 2, including neurologic complications such as dizziness (27% of patients), cognitive changes (4%), and weight gain, which is most commonly reported as Grade 3. No treatment-related mortality was noted. The study revealed a CR of 7% and a PR of 50%. Based on the report, the FDA approved entrectinib for adult and pediatric populations in August 2019, and subsequently, the European Medicines Agency also approved entrectinib in 2020 due to its safety profile [33].

6. Second-Generation NTRK Inhibitors

6.1. Repotrectinib

Due to the limited durability and resistant mutations against first-generation inhibitors, second-generation inhibitor trials have started to overcome the difficulties. Repotrectinib has a smaller molecular weight and a more compact macrocyclic structure than the first generation [34]. Repotrectinib is a small compound compared to other inhibitors created to accommodate the bulky, positively charged arginine side chain in the solvent front without steric clashes. In phases 1 and 2 of the TRIDENT-1 study (NCT03093116), with 40 populations who received repotrectinib, the ORR was 41–62% [35]. Common side effects from the study include mild Grade 1 ataxia, paresthesia, nausea, perioral numbness, and dysgeusia—the FDA approved repotrectinib to treat patients with advanced solid tumors due to the safety profile of the medication.

6.2. Selitrectinib

Although the major clinical trials of selitretinib, including NCT03206931 and NT03215511 are ongoing, most case reports reported that selitrectinib might be an efficient medication for solid malignancies [36,37]. Additionally, patients resistant to entrectinib through the NTRK3 G623R mutation revealed good responses with selitrectinib per the 2021 report [38].

6.3. Taletrectinib

Taletrectinib is a newly emerged ROS1/NTRK kinase inhibitor with high activity against the G2031R solvent-front mutation compared to other inhibitors [39]. According to the published report of the first human phase 1 study (TRUST) in 2020 with 46 patient populations, the confirmed objective response rate was 33.3% [40]. Most common treatment-related adverse events, such as nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%), were noted. However, there is no clinical data on the effect of taletrectinib on overcoming resistance to first-generation inhibitors. Table 2 summarizes the overall clinical trials, response results, and commonly noted side effects per trial.

6.4. Other Agents

Several multi-target tyrosine kinase inhibitors (TKIs) with varying inhibitory activity against tropomyosin receptor kinase (TRK) have received approvals for indications beyond the treatment of patients with NTRK fusions. Crizotinib, initially designed as a MET inhibitor, was later recognized as an inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and TRK. However, its affinity for TRK is significantly lower than for MET, ALK, and ROS1. It is approved for treating ALK- and ROS1-rearranged non-small cell lung cancer (NSCLC) [41].
Cabozantinib, approved by the FDA for renal cell carcinoma and medullary thyroid carcinoma, targets multiple receptor tyrosine kinases, including MET, RET, AXL, TRKA, and TRKB [42,43,44]. Ponatinib, originally developed as a BCR-ABL1 inhibitor for chronic myelogenous leukemia, has demonstrated efficacy against most BCR-ABL1 resistance mutations and has shown potential in suppressing the growth of NTRK fusion-positive tumors in preclinical trials [45,46].
Nintedanib, recognized as an anti-angiogenic drug and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, has also exhibited inhibitory effects on platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and TRK kinases [47,48].
The clinical activity of these multi-target TRK inhibitors in patients with NTRK fusion-positive cancers is not extensively characterized. However, well-established developments in larotrectinib, entrectinib, and second-generation inhibitors like repotrectinib and taletrectinib provide promising avenues for treating cancers harboring NTRK fusions.

6.5. Mechanisms of Resistance to NTRK Inhibitors

However, resistance to first-generation inhibitors was identified through the mutations of NTRK1 gene fusion proteins such as G667C and G595R [49]. In a 2021 report, one patient with mammary secretory carcinoma of the parotic gland and the ETV6-NTRK3 fusion reported secondary resistance to entrectinib through the NTRK3 G623R mutation [38]. Second-generation inhibitors, which include selitrectinib and repotrectinib, have emerged to overcome the mechanism of acquired resistance. However, recent trials indicated that resistance against the second generation develops through the mutation of TRK proteins such as xDFG [50].

6.6. Overall Side Effects and Effects of TRK Inhibition

According to Smeyne RJ et al., in a 1994 trial, NTRK1-null mice lacking most sympathetic neurons did not exhibit nociceptive and temperature sensations and eventually passed away within a month due to severe sensory and sympathetic neuropathies [51]. In comparison, NTRK2 knockout mice, lacking motor neurons or dorsal root and trigeminal ganglia neurons, died perinatally due to a lack of eating [52]. NTRK3-null mice also exhibited deficits in the quality and quantity of motor neurons and deficits in a population of dorsal root ganglia neurons, resulting in abnormal movements and posture [53]. Homozygous disruption of the NTRK2 gene revealed an increase in apoptosis of endothelial cells and a decreased number of intramyocardial blood vessels. In contrast, targeted deletion of all TRKC isoforms in mice led to severe cardiac deficiencies, including atrial, ventricular, and valvular defects, resulting in animal death in the early postnatal period [54].
However, according to clinical studies conducted in humans, it is remarkable that first- and second-generation NTRK inhibitors are very well-tolerated. Side effects are usually manageable and NTRK inhibitors have proven effective in malignancies that are positive for NTRK gene fusion. The most common side effects were typically gastrointestinal, and 30% of patients developed dizziness, in addition to other central nervous system side effects like ataxia, paresthesia, and perioral numbness. According to the study by Qin et al., 10% of 218 patients displayed weight gain, and 12% developed anemia [55]. Other non-specific side effects, such as fatigue and elevated liver enzymes, are also commonly noted among patients treated with NTRK inhibitors. Importantly, the mentioned side effects are known to be reversible after discontinuing the medications.

7. Role of NTRK Inhibitors in Various Types of Cancers and Adverse Effects

NTRK gene fusions have been identified across a spectrum of malignancies, encompassing diverse cancer types such as lung cancer, melanoma, colorectal cancer, thyroid cancer, and leukemia. In contrast to rare cancers, where NTRK gene alterations are detected in approximately 80% of cases, the prevalence of gene fusions in common solid malignancies is markedly lower, ranging from 5 to 25%. Notably, in prevalent solid tumors like lung and breast cancers, the frequency of NTRK gene fusions is less than 1% [56].
Rare tumors exhibiting a substantial prevalence of NTRK fusion genes include carcinoma ex-pleomorphic adenoma, secretory breast carcinoma, congenital mesoblastic nephroma, and infantile fibrosarcoma. Despite the infrequency of NTRK gene fusions in common solid tumors, their identification holds paramount importance due to the emerging role of NTRK inhibitors in targeted therapeutic interventions.
This review study aims to comprehensively discuss recent applications of NTRK inhibitor therapy in selected common malignancies. By exploring the therapeutic landscape of NTRK inhibitors in prevalent cancers, we endeavor to contribute to the evolving understanding of their efficacy and potential implications in oncology practice.

7.1. NTRK Gene Fusion in Lung Cancer

Among lung cancers, especially non-small cell lung cancer (NSCLC), NTRK gene fusions can be found only 0.5% of the time. However, gene fusion can also be found in other subtypes like neuroendocrine carcinoma and sarcomatoid tumors of the lung [57]. NTRK1 and NTRK2 are commonly expressed in squamous cell carcinoma compared to adenocarcinoma and small cell lung cancer. First-generation inhibitors have been proven to be a practical and durable therapy for managing NSCLC.
For example, according to the Drilon et al. trial, which published results in 20 patients with NTRK fusion-positive lung cancer, the ORR among 15 evaluable patients evaluated by investigator assessment was 73% (95% CI, 45–92); the CR was 7%, the PR was 67%, 20% had stable disease, and 7% had progressive disease as the best response [58]. The median duration of response, PFS, and overall survival were a total of 33.9 months (95% CI, 5.6–33.9), 35.4 months (95% CI, 5.3–35.4), and 40.7 months (95% CI, 17.2-not estimable), respectively. The ORR among patients with CNS metastases at baseline was 63% (95% CI: 25–91) [58]. In a recent report about ctDNA analysis in 2023 with a patient treated with larotrectinib in two clinical trials, the ORR was 83% (95% CI 61–95) with an extended survival benefit and a favorable safety profile in a patient with advanced lung cancer [59].
Most adverse events were considered as Grade 1 or 2. Nevertheless, resistance may develop due to fusion variants such as TPM3-NTRK1. Similarly, EGFR-TKI and gene fusion partners, including ETV6 and SQTTM1, have demonstrated resistance to third-generation inhibitors [60].

7.2. NTRK Gene Fusion in Colorectal Cancer

In approximately 0.7% of colon cancers, NTRK gene fusion, especially NTRK1 and NTRK3, is found alongside APC and TP53 gene aberrations and RAS/BRAF gene alterations [61]. The TPM3-NTRK1 rearrangement is commonly seen [62]. NTRK is prevalent in females with a right-sided primary colorectal tumor, RAS/RAF WT status, and MSI phenotype, according to data from the phase 2 NAVIGATE trial, which produces various responses in patients to larotrectinib with the gene-positive fusion, and which is locally advanced, and in metastatic GI cancers, especially in colorectal cancer with an ORR which is 3% and a partial response rate of 30% [63,64]. Therefore, it is crucial to identify NTRK fusions in GI malignancy patients, especially those with high microsatellite instability rates [65].

7.3. NTRK Gene Fusion in Central Nervous System Malignancies

Central Nervous System (CNS) tumors, such as low- and high-grade gliomas, are distinguished from other solid malignancies by the quantity of NTRK gene fusion [66]. The NTRK1/TRKA fusion has been linked to an improved prognosis and an increased likelihood of tumor regression. The NTRK2/TRKB fusion has been found to be detrimental in certain tumors [66]. Gliomas, characterized by NTRK gene expression, tend to affect multiple regions of the nervous system, particularly the hemisphere and frequently have an aggressive clinical course. The cohort study conducted by Torre et al. identified the detailed anatomical distribution of NTRK fusions, revealing a predominant occurrence in the hemispheric region (66.7%). Additionally, NTRK fusions were observed in the brainstem (9.5%), cerebellum (7.1%), and optic nerve/suprasellar region/deep grey nuclei (4.8%). However, among pediatric NTRK-fused gliomas, the distribution appears to be more diverse [67].
In CNS tumors, the frequency of NTRK2 (11% of GBM) and NTRK1 (1% of GBM) fusions exceeds that of NTRK3. Notably, first-generation inhibitors have exhibited the ability to cross the blood–brain barrier, with larotrectinib demonstrating remarkable specificity for NTRK fusions and notable efficacy against CNS tumors [68]. Given the limitations of surgical resection and radiotherapy in treating brain malignancies, identifying oncogenes such as NTRK gene fusions becomes crucial. The identification and targeting of NTRK fusions may offer critical clinical advantages [69]. Additional research in cancer neuroscience and clinical trials is required to explore the full potential of NTRK-targeted therapies in effectively treating CNS cancers.

7.4. NTRK Gene Fusion in Thyroid Cancers

Thyroid cancer, like other solid tumors, has few NTRK fusions. NTRK rearrangement in the TKD of the NTRK1 gene can arise in thyroid cancer, particularly papillary thyroid carcinoma. Furthermore, a gene mutation known as the ETV-NTRK3 fusion is present in around 14.5% of patients diagnosed with thyroid cancer due to radiation exposure following the Chornobyl nuclear accident [70]. IRF2BP2-NTRK3 is also spotted in papillary thyroid carcinoma [61]. In a report in 2023 combining the three clinical trials with larotrectinib (NCT02576431, NCT02122913, NCT02637687) with 30 adult patients with fusion-positive thyroid cancers, the ORR was 63% (95% CI 44–80%), the CR was 53%, the PR was 17%, and 13% had progressive disease [6,28,29,71]. Larotrectinib produced a rapid and durable response, extended survival, and a favorable safety profile in this trial.

7.5. NTRK Gene Fusion in Hematological Malignancies

Hematological malignancies, including acute myeloid and lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), and Philadelphia-positive ALL, frequently have the NTRK-ETV6 fusion. Taylor et al. reported that larotrectinib, a first-generation inhibitor, reduced expression of the fusion gene while inhibiting TRK activity in patients with NTRK2-ETV6 variants associated with histiocytosis and complex myeloma [72].
Notably, TP53 cell lines are more sensitive to the first-generation inhibitor [73]. Despite these promising results, TRK aberrations have been shown to have reactivity against the therapeutic target, limiting the efficacy of clinical benefits in certain hematological tumors. Further studies and research are needed to fully understand the potential clinical benefits of NTRK therapy in various hematological malignancies.

7.6. NTRK Gene Fusion in Sarcomas

Among soft tissue sarcomas, the predominant characterization of infantile fibrosarcoma and lipofibromatosis-like neural tumors revolves around ETV6-NTRK3 fusions and NTRK1 gene rearrangements [74,75]. In a minority of cases, NTRK3-negative infantile fibrosarcomas have been documented to exhibit NTRK1 gene rearrangements instead [76]. Chiang et al.’s research highlights the occurrence of NTRK gene rearrangements within a subset of undifferentiated uterine sarcomas displaying fibrosarcoma-like morphology [77]. Kojima et al. also used immunohistochemistry to discover CD30 expression in mesenchymal tumors with kinase gene fusions, including NTRK-rearranged tumors and BRAF, RAF1, or RET fusion tumors [78]. Xu et al. highlighted molecular testing for kinase fusions in spindle cell neoplasms exhibiting specific features, emphasizing the significance of pan-TRK positivity in NTRK fusions [79]. Incorporating the NTRK fusion into the existing diagnostic evaluation of sarcoma patients presents a unique challenge due to the biomarker’s rarity. IHC serves as a valuable initial screening tool, and implementing targeted MPS panels, specifically designed to identify NTRK gene fusions, in routine genome-wide MPS for sarcomas is cost-effective, given the limited number of additional genomic alterations requiring testing [80].

7.7. NTRK Gene Fusion in Melanocytic Tumors

NTRK fusions have a diagnostic and classification impact among melanocytic tumors. Among melanocytic neoplasms, Spitz tumors are one subgroup with distinct morphological features that tend to affect young individuals [81,82]. Yeh et al. identified ETV6-NTRK3, MYO5A-NTRK3, and MYH9-NTRK3 fusions in Spitz tumors [83]. Additionally, Yeh et al. report 38 Spitz tumors with NTRK1 fusions with distinctive histopathologic features which is helpful in diagnosis and helps prioritize case selection for molecular testing in patients that need targeted therapy [84]. Atypical Spitz tumors (AST) deviate from stereotypical Spitz tumors due to atypical features and are now regarded as an intermediate category of melanocytic tumors with uncertain malignant potential. Cappellesso et al., with a series of 180 AST screens with pan-TRK IHC and confirmed with FISH, detected NTRK 1 and NTRK 3 fusions [85].
Among melanocytic tumors, acral and mucosal melanomas are aggressive subtypes with a significantly lower somatic mutation burden than cutaneous melanomas but more frequent genetic variations, focused gene amplifications, and structural alterations. NTRK fusions are common in spitzoid melanoma, with a prevalence of 21–29% compared to <1% in cutaneous or mucosal melanoma and 2.5% in acral melanoma, which reveals that fusion proteins are mutually exclusive for most common oncogenic drivers such as BRAF or NRAS [86]. The frequency of the NTRK fusion gene, NTRK1, NTRK2, and NTRK3 in metastatic non-acral cutaneous melanoma is approximately 0.8% and 0.9% in mucosal and para-mucosal melanomas [87]. The meta-analysis by Wang et al. focuses on different gene mutations such as MITF, PTEN, ATM, PRKN, and BRAF V600E mutations in sacral melanoma by shedding new light on the pathogenesis and broadening the catalog of therapeutic targets for this difficult-to-treat cancer [88].

7.8. NTRK Gene Fusion in Salivary Gland Tumors

The presence of NTRK gene fusions has been specifically observed in rare tumors, particularly in secretory carcinomas of the breast and salivary gland, indicating a unique prevalence. The most common fusion variant within the category of salivary gland carcinomas is ETV6-NTRK3. This fusion subtype has been consistently identified in different types of salivary gland carcinomas, including two cases of secretory carcinoma and one case of adenocarcinoma [89]. The frequent presence of the ETV6-NTRK3 fusion in salivary gland tumors highlights its importance as a possible diagnostic indicator and target for medical treatment. In order to gain a better understanding of the complex molecular mechanisms and medical significance of NTRK gene fusions in salivary gland tumors, it is essential to conduct extensive clinical research and molecular profiling studies.

7.9. Other Malignancies

The fusion of NTRK3 and ETV6 is mainly linked to around 90% of instances of rare secretory breast carcinoma, along with a specific group of triple-negative breast cancer subtypes [90]. Moreover, NTRK fusion genes exhibit a notable prevalence in specific pediatric malignancies such as congenital melanocytic nevus (CMN) and secretory breast carcinoma (SBC). Irrespective of tumor histology, the therapeutic response to first-generation inhibitors has demonstrated remarkable efficacy, with a superior response rate of 75% observed in 73% of cases within a 6-month timeframe, particularly with entrectinib. Notably, although slightly reduced compared to the 6-month response, an overall response rate (ORR) of 57% has been documented in 68% of patients [6]. These findings underscore the broad therapeutic potential of targeting NTRK fusion genes across diverse malignancies and highlight the promising clinical outcomes achievable with targeted NTRK inhibition strategies. Additional research is necessary to better understand the mechanisms underlying the response to NTRK inhibitors and the optimization of treatment protocols are warranted to maximize therapeutic efficacy and patient outcomes.

7.10. Future Directions and Challenges

Beginning with the NAVIGATE trials, multiple clinical trials have demonstrated the greater efficacy and superior outcomes of NTRK inhibitors in different types of solid tumors and hematological malignancies. Due to the rarity of NTRK gene fusions in most malignancies, testing for it may be challenging. In addition, selecting reliable testing may be difficult due to sensitivity and specificity issues with specific tests, which necessitate confirmation tests, sample limitations, and the expense of the tests.
However, patients with NTRK mutations and amplifications cannot receive inhibitor therapy due to other non-actionable genetic aberrations [91]. NTRK inhibitor therapy could be costly and difficult to evaluate in some regions. On the other hand, we expect the cost to be reasonable based on the required dose compared to conventional chemotherapy for specific cancer types. Moreover, a large generalized clinical trial might be required to investigate details of long-term side effects, estimate the total duration of therapy, and see whether it is beneficial with combined treatment or single treatment.
Developing more predictive and sensitive biomarkers could also be helpful in further tests for gene fusion. Despite that, efforts have been made to expand patients’ access to genetic testing and targeted therapies to ensure equitable and widespread implementation. Regardless, NTRK therapy has shown successful outcomes in many clinical trials, highlighting the critical aspect of comprehensive genomic profiling in cancer patients. In the future, the treatment will be applied widely.

8. Conclusions

NTRK therapy has emerged as a promising treatment option for cancer patients with NTRK fusion-positive tumors. Following the landmark NAVIGATE clinical trials, the development of first- and second-generation NTRK inhibitors transformed the treatment landscape, providing superior clinical outcomes, greater quality of life, and longer survival rates than traditional TKIs. The recommendation for outpatient settings is to use comprehensive nucleic acid-based profiling and complementary immunohistochemistry (IHC) assays to detect abnormal gene fusions. However, issues such as limited access to testing and associated treatment costs continue. Despite these challenges, there is a compelling need for additional clinical trials to investigate the long-term side effects and comparative efficacy of NTRK therapy versus conventional chemotherapy or combination therapies. These endeavors are critical for comprehending the overall potential of NTRK therapy while addressing existing healthcare system barriers. Such initiatives represent a paradigm shift in precision medicine and offer optimism towards the future of cancer treatment.

Author Contributions

N.W.Y.T.; M.M.; A.M.A.-P.; methodology, validation, formal analysis, writing—original draft preparation. L.E.R.; Investigation, data curation, review and editing, supervision. A.M.H.; A.S.; project administration, supervision. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. National Cancer Institute. FDA Approves Entrectinib for NTRK Fusion Cancers. Cancer Currents Blog. 16 August 2019. Available online: https://www.cancer.gov/news-events/cancer-currents-blog/2019/fda-entrectinib-ntrk-fusion (accessed on 1 January 2020).
  2. Drilon, A.; Siena, S.; Ou, S.I.; Patel, M.; Ahn, M.J.; Lee, J.; Bauer, T.M.; Farago, A.F.; Wheler, J.J.; Liu, S.V.; et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017, 7, 400–409. [Google Scholar] [CrossRef] [PubMed]
  3. Lannon, C.L.; Sorensen, P.H. ETV6-NTRK3: A chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin. Cancer Biol. 2005, 15, 215–223. [Google Scholar] [CrossRef] [PubMed]
  4. Pulciani, S.; Santos, E.; Lauver, A.V.; Long, L.K.; Aaronson, S.A.; Barbacid, M. Oncogenes in solid human tumours. Nature 1982, 300, 539–542. [Google Scholar] [CrossRef] [PubMed]
  5. Ruiz-Cordero, R.; Ng, D.L. Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer. Cancer Cytopathol. 2020, 128, 775–779. [Google Scholar] [CrossRef] [PubMed]
  6. Drilon, A.; Laetsch, T.W.; Kummar, S.; DuBois, S.G.; Lassen, U.N.; Demetri, G.D.; Nathenson, M.; Doebele, R.C.; Farago, A.F.; Pappo, A.S.; et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N. Engl. J. Med. 2018, 378, 731–739. [Google Scholar] [CrossRef]
  7. Marcus, L.; Donoghue, M.; Aungst, S.; Myers, C.E.; Helms, W.S.; Shen, G.; Zhao, H.; Stephens, O.; Keegan, P.; Pazdur, R. FDA Approval Summary: Entrectinib for the Treatment of NTRK gene Fusion Solid Tumors. Clin. Cancer Res. 2021, 27, 928–932. [Google Scholar] [CrossRef]
  8. Connor, A.; Perez-Ordoñez, B.; Shago, M.; Skálová, A.; Weinreb, I. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: Expanded morphologic and immunohistochemical spectrum of a recently described entity. Am. J. Surg. Pathol. 2012, 36, 27–34. [Google Scholar] [CrossRef]
  9. Skálová, A.; Vanecek, T.; Simpson, R.H.; Laco, J.; Majewska, H.; Baneckova, M.; Steiner, P.; Michal, M. Mammary Analogue Secretory Carcinoma of Salivary Glands: Molecular Analysis of 25 ETV6 Gene Rearranged Tumors with Lack of Detection of Classical ETV6-NTRK3 Fusion Transcript by Standard RT-PCR: Report of 4 Cases Harboring ETV6-X Gene Fusion. Am. J. Surg. Pathol. 2016, 40, 3–13. [Google Scholar] [CrossRef]
  10. Murphy, D.A.; Ely, H.A.; Shoemaker, R.; Boomer, A.; Culver, B.P.; Hoskins, I.; Haimes, J.D.; Walters, R.D.; Fernandez, D.; Stahl, J.A.; et al. Detecting Gene Rearrangements in Patient Populations Through a 2-Step Diagnostic Test Comprised of Rapid IHC Enrichment Followed by Sensitive Next-Generation Sequencing. Appl. Immunohistochem. Mol. Morphol. 2017, 25, 513–523. [Google Scholar] [CrossRef]
  11. Wong, D.; Yip, S.; Sorensen, P.H. Methods for Identifying Patients with Tropomyosin Receptor Kinase (TRK) Fusion Cancer. Pathol. Oncol. Res. 2020, 26, 1385–1399. [Google Scholar] [CrossRef] [PubMed]
  12. Martin-Zanca, D.; Oskam, R.; Mitra, G.; Copeland, T.; Barbacid, M. Molecular and biochemical characterization of the human trk proto-oncogene. Mol. Cell Biol. 1989, 9, 24–33. [Google Scholar] [CrossRef] [PubMed]
  13. Klein, R.; Jing, S.Q.; Nanduri, V.; O’Rourke, E.; Barbacid, M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 1991, 65, 189–197. [Google Scholar] [CrossRef] [PubMed]
  14. Soppet, D.; Escandon, E.; Maragos, J.; Middlemas, D.S.; Reid, S.W.; Blair, J.; Burton, L.E.; Stanton, B.R.; Kaplan, D.R.; Hunter, T.; et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 1991, 65, 895–903. [Google Scholar] [CrossRef] [PubMed]
  15. Frade, J.M.; Barde, Y.A. Nerve growth factor: Two receptors, multiple functions. BioEssays: News and reviews in molecular, cellular and developmental biology. Bioessays 1998, 20, 137–145. [Google Scholar] [CrossRef]
  16. Patel, T.D.; Jackman, A.; Rice, F.L.; Kucera, J.; Snider, W.D. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 2000, 25, 345–357, Erratum in Neuron 2003, 37, 183. [Google Scholar] [CrossRef] [PubMed]
  17. Teng, H.K.; Teng, K.K.; Lee, R.; Wright, S.; Tevar, S.; Almeida, R.D.; Kermani, P.; Torkin, R.; Chen, Z.Y.; Lee, F.S.; et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. Off. J. Soc. Neurosci. 2005, 25, 5455–5463. [Google Scholar] [CrossRef]
  18. Valent, A.; Danglot, G.; Bernheim, A. Mapping of the tyrosine kinase receptors trkA (NTRK1), trkB (NTRK2) and trkC(NTRK3) to human chromosomes 1q22, 9q22 and 15q25 by fluorescence in situ hybridization. Eur. J. Hum. Genet. 1997, 5, 102–104. [Google Scholar] [CrossRef]
  19. Bertrand, T.; Kothe, M.; Liu, J.; Dupuy, A.; Rak, A.; Berne, P.F.; Davis, S.; Gladysheva, T.; Valtre, C.; Crenne, J.Y.; et al. The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. J. Mol. Biol. 2012, 423, 439–453. [Google Scholar] [CrossRef]
  20. Rajagopal, R.; Chen, Z.Y.; Lee, F.S.; Chao, M.V. Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. J. Neurosci. 2004, 24, 6650–6658. [Google Scholar] [CrossRef]
  21. Geiger, T.R.; Song, J.Y.; Rosado, A.; Peeper, D.S. Functional characterization of human cancer-derived TRKB mutations. PLoS ONE 2011, 6, e16871. [Google Scholar] [CrossRef]
  22. Harada, T.; Yatabe, Y.; Takeshita, M.; Koga, T.; Yano, T.; Wang, Y.; Giaccone, G. Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2011, 17, 2638–2645. [Google Scholar] [CrossRef]
  23. Miranda, C.; Mazzoni, M.; Sensi, M.; Pierotti, M.A.; Greco, A. Functional characterization of NTRK1 mutations identified in melanoma. Genes Chromosomes Cancer 2014, 53, 875–880. [Google Scholar] [CrossRef]
  24. Tomasson, M.H.; Xiang, Z.; Walgren, R.; Zhao, Y.; Kasai, Y.; Miner, T.; Ries, R.E.; Lubman, O.; Fremont, D.H.; McLellan, M.D.; et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 2008, 111, 4797–4808. [Google Scholar] [CrossRef]
  25. Cocco, E.; Scaltriti, M.; Drilon, A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev. Clin. Oncol. 2018, 15, 731–747. [Google Scholar] [CrossRef] [PubMed]
  26. Drilon, A.; Li, G.; Dogan, S.; Gounder, M.; Shen, R.; Arcila, M.; Wang, L.; Hyman, D.M.; Hechtman, J.; Wei, G.; et al. What hides behind the MASC: Clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2016, 27, 920–926. [Google Scholar] [CrossRef]
  27. Dunn, D.B. Larotrectinib and Entrectinib: TRK Inhibitors for the Treatment of Pediatric and Adult Patients with NTRK Gene Fusion. J. Adv. Pract. Oncol. 2020, 11, 418–423. [Google Scholar] [CrossRef] [PubMed]
  28. Doebele, R.C.; Davis, L.E.; Vaishnavi, A.; Le, A.T.; Estrada-Bernal, A.; Keysar, S.; Jimeno, A.; Varella-Garcia, M.; Aisner, D.L.; Li, Y.; et al. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015, 5, 1049–1057. [Google Scholar] [CrossRef]
  29. Laetsch, T.W.; DuBois, S.G.; Mascarenhas, L.; Turpin, B.; Federman, N.; Albert, C.M.; Nagasubramanian, R.; Davis, J.L.; Rudzinski, E.; Feraco, A.M.; et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: Phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018, 19, 705–714. [Google Scholar] [CrossRef] [PubMed]
  30. Lin, J.J.; Kummar, S.; Tan, D.S.-W.; Lassen, U.N.; Leyvraz, S.; Liu, Y.; Moreno, V.; Patel, J.D.; Rosen, L.S.; Solomon, B.M.; et al. Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer. J. Clin. Oncol. 2021, 39, 9109. [Google Scholar] [CrossRef]
  31. Rolfo, C.; Ruiz, R.; Giovannetti, E.; Gil-Bazo, I.; Russo, A.; Passiglia, F.; Giallombardo, M.; Peeters, M.; Raez, L. Entrectinib: A potent new TRK, ROS1, and ALK inhibitor. Expert Opin. Investig. Drugs 2015, 24, 1493–1500. [Google Scholar] [CrossRef]
  32. Doebele, R.C.; Drilon, A.; Paz-Ares, L.; Siena, S.; Shaw, A.T.; Farago, A.F.; Blakely, C.M.; Seto, T.; Cho, B.C.; Tosi, D.; et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020, 21, 271–282. [Google Scholar] [CrossRef]
  33. Paz-Ares, L.; Barlesi, F.; Siena, S.; Ahn, M.J.; Drilon, A.; Conley, A.; Rolfo, C.; Wolf, J.; Seto, T.; Doebele, R.; et al. Patient-reported outcomes from STARTRK-2: A global phase II basket study of entrectinib for ROS1 fusion-positive non-small-cell lung cancer and NTRK fusion-positive solid tumours. ESMO Open 2021, 6, 100113. [Google Scholar] [CrossRef] [PubMed]
  34. Murray, B.W.; Rogers, E.; Zhai, D.; Deng, W.; Chen, X.; Sprengeler, P.A.; Zhang, X.; Graber, A.; Reich, S.H.; Stopatschinskaja, S.; et al. Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Mol. Cancer Ther. 2021, 20, 2446–2456. [Google Scholar] [CrossRef] [PubMed]
  35. Cho, B.C.; Drilon, A.E.; Doebele, R.C.; Kim, D.W.; Lin, J.J.; Lee, J.; Ahn, M.J.; Zhu, V.W.; Ejadi, S.; Camidge, D.R. Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1 fusion-positive non-small cell lung cancer (TRIDENT-1 study). J. Clin. Oncol. 2019, 37 (Suppl. 15), 9011. [Google Scholar] [CrossRef]
  36. Hyman, D.; Kummar, S.; Farago, A.; Geoerger, B.; Mau-Sorensen, M.; Taylor, M.; Garralda, E.; Nagasubramanian, R.; Natheson, M.; Song, L.; et al. Abstract CT127: Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). Cancer Res. 2019, 79 (Suppl. 13), CT127. [Google Scholar] [CrossRef]
  37. National Institutes of Health (NIH). ClinicalTrials.gov. A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults that May Treat Cancer. Available online: https://www.clinicaltrials.gov/ct2/show/NCT03215511?cond=LOXO-195&rank=1 (accessed on 11 April 2019).
  38. Florou, V.; Nevala-Plagemann, C.; Whisenant, J.; Maeda, P.; Gilcrease, G.W.; Garrido-Laguna, I. Clinical Activity of Selitrectinib in a Patient with Mammary Analogue Secretory Carcinoma of the Parotid Gland with Secondary Resistance to Entrectinib. J. Natl. Compr. Cancer Netw. 2021, 19, 478–482. [Google Scholar] [CrossRef] [PubMed]
  39. Katayama, R.; Gong, B.; Togashi, N.; Miyamoto, M.; Kiga, M.; Iwasaki, S.; Kamai, Y.; Tominaga, Y.; Takeda, Y.; Kagoshima, Y.; et al. The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Nat. Commun. 2019, 10, 3604. [Google Scholar] [CrossRef]
  40. Zhou, C.; Fan, H.; Wang, Y.; Wu, H.; Yang, N.; Li, K.; Wang, X.; Qin, X.; Yu, Q.; Fang, Y.; et al. Taletrectinib (AB-106; DS-6051b) in metastatic non-small cell lung cancer (NSCLC) patients with ROS1 fusion: Preliminary results of TRUST. J. Clin. Oncol. 2021, 39 (Suppl. 15). [Google Scholar] [CrossRef]
  41. Kazandjian, D.; Blumenthal, G.M.; Luo, L.; He, K.; Fran, I.; Lemery, S.; Pazdur, R. Benefit-Risk Summary of Crizotinib for the Treatment of Patients with ROS1 Alteration-Positive, Metastatic Non-Small Cell Lung Cancer. Oncologist 2016, 21, 974–980. [Google Scholar] [CrossRef]
  42. Singh, H.; Brave, M.; Beaver, J.A.; Cheng, J.; Tang, S.; Zahalka, E.; Palmby, T.R.; Venugopal, R.; Song, P.; Liu, Q.I.; et al. Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2017, 23, 330–335. [Google Scholar] [CrossRef]
  43. Zou, H.Y.; Li, Q.; Lee, J.H.; Arango, M.E.; McDonnell, S.R.; Yamazaki, S.; Koudriakova, T.B.; Alton, G.; Cui, J.J.; Kung, P.P.; et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007, 67, 4408–4417. [Google Scholar] [CrossRef]
  44. Bowles, D.W.; Kessler, E.R.; Jimeno, A. Multi-targeted tyrosine kinase inhibitors in clinical development: Focus on XL-184 (cabozantinib). Drugs Today 2011, 47, 857–868. [Google Scholar] [CrossRef]
  45. Shamroe, C.L.; Comeau, J.M. Ponatinib: A new tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann. Pharmacother. 2013, 47, 1540–1546. [Google Scholar] [CrossRef]
  46. O’Hare, T.; Shakespeare, W.C.; Zhu, X.; Eide, C.A.; Rivera, V.M.; Wang, F.; Adrian, L.T.; Zhou, T.; Huang, W.S.; Xu, Q.; et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009, 16, 401–412. [Google Scholar] [CrossRef]
  47. Karimi-Shah, B.A.; Chowdhury, B.A. Forced vital capacity in idiopathic pulmonary fibrosis--FDA review of pirfenidone and nintedanib. N. Engl. J. Med. 2015, 372, 1189–1191. [Google Scholar] [CrossRef]
  48. Hilberg, F.; Roth, G.J.; Krssak, M.; Kautschitsch, S.; Sommergruber, W.; Tontsch-Grunt, U.; Garin-Chesa, P.; Bader, G.; Zoephel, A.; Quant, J.; et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008, 68, 4774–4782. [Google Scholar] [CrossRef] [PubMed]
  49. Fuse, M.J.; Okada, K.; Oh-Hara, T.; Ogura, H.; Fujita, N.; Katayama, R. Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers. Mol. Cancer Ther. 2017, 16, 2130–2143. [Google Scholar] [CrossRef] [PubMed]
  50. Russo, M.; Misale, S.; Wei, G.; Siravegna, G.; Crisafulli, G.; Lazzari, L.; Corti, G.; Rospo, G.; Novara, L.; Mussolin, B.; et al. Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer. Cancer Discov. 2016, 6, 36–44. [Google Scholar] [CrossRef] [PubMed]
  51. Smeyne, R.J.; Klein, R.; Schnapp, A.; Long, L.K.; Bryant, S.; Lewin, A.; Lira, S.A.; Barbacid, M. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 1994, 368, 246–249. [Google Scholar] [CrossRef]
  52. Klein, R.; Smeyne, R.J.; Wurst, W.; Long, L.K.; Auerbach, B.A.; Joyner, A.L.; Barbacid, M. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 1993, 75, 113–122. [Google Scholar] [CrossRef]
  53. Klein, R.; Silos-Santiago, I.; Smeyne, R.J.; Lira, S.A.; Brambilla, R.; Bryant, S.; Zhang, L.; Snider, W.D.; Barbacid, M. Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Nature 1994, 368, 249–251. [Google Scholar] [CrossRef]
  54. Tessarollo, L.; Tsoulfas, P.; Donovan, M.J.; Palko, M.E.; Blair-Flynn, J.; Hempstead, B.L.; Parada, L.F. Targeted deletion of all isoforms of the trkC gene suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and implicates trkC in normal cardiogenesis. Proc. Natl. Acad. Sci. USA 1997, 94, 14776–14781. [Google Scholar] [CrossRef]
  55. Qin, H.; Patel, M.R. The Challenge and Opportunity of NTRK Inhibitors in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2022, 23, 2916. [Google Scholar] [CrossRef]
  56. Okamura, R.; Boichard, A.; Kato, S.; Sicklick, J.K.; Bazhenova, L.; Kurzrock, R. Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics. JCO Precis. Oncol. 2018, 2, 1–20. [Google Scholar] [CrossRef]
  57. Farago, A.F.; Taylor, M.S.; Doebele, R.C.; Zhu, V.W.; Kummar, S.; Spira, A.I.; Boyle, T.A.; Haura, E.B.; Arcila, M.E.; Benayed, R.; et al. Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an NTRK Gene Fusion. JCO Precis. Oncol. 2018, 2, 1–12. [Google Scholar] [CrossRef]
  58. Drilon, A.; Tan, D.S.W.; Lassen, U.N.; Leyvraz, S.; Liu, Y.; Patel, J.D.; Rosen, L.; Solomon, B.; Norenberg, R.; Dima, L.; et al. Efficacy and Safety of Larotrectinib in Patients with Tropomyosin Receptor Kinase Fusion-Positive Lung Cancers. JCO Precis. Oncol. 2022, 6, e2100418. [Google Scholar] [CrossRef]
  59. Hoejgaard, M.; Drilon, A.; Lin, J.J.; Kummar, S.; Tan, D.S.W.; Patel, J.; Leyvraz, S.; Garcia, V.M.; Rosen, L.S.; Solomon, B.; et al. 15MO Efficacy and ctDNA analysis in an updated cohort of patients with TRK fusion lung cancer treated with larotrectinib. J. Thorac. Oncol. 2023, 18, S48–S49. [Google Scholar] [CrossRef]
  60. Sigal, D.S.; Bhangoo, M.S.; Hermel, J.A.; Pavlick, D.C.; Frampton, G.; Miller, V.A.; Ross, J.S.; Ali, S.M. Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors. Oncotarget 2018, 9, 35809–35812. [Google Scholar] [CrossRef] [PubMed]
  61. Wang, H.; Li, Z.W.; Ou, Q.; Wu, X.; Nagasaka, M.; Shao, Y.; Ou, S.I.; Yang, Y. NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability. Cancer Med. 2022, 11, 2541–2549. [Google Scholar] [CrossRef] [PubMed]
  62. Zhao, X.; Kotch, C.; Fox, E.; Surrey, L.F.; Wertheim, G.B.; Baloch, Z.W.; Lin, F.; Pillai, V.; Luo, M.; Kreiger, P.A.; et al. NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome. JCO Precis. Oncol. 2021, 1, 204–214. [Google Scholar] [CrossRef] [PubMed]
  63. Pietrantonio, F.; Di Nicolantonio, F.; Schrock, A.B.; Lee, J.; Tejpar, S.; Sartore-Bianchi, A.; Hechtman, J.F.; Christiansen, J.; Novara, L.; Tebbutt, N.; et al. ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. J. Natl. Cancer Inst. 2017, 109, djx089. [Google Scholar] [CrossRef]
  64. Garralda, E.; Hong, D.S.; Xu, R.; Deeken, J.; Italiano, A.; Liu, T.; Ferrandiz, A.; Patel, J.; Lee, D.; Chung, H.; et al. Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion gastrointestinal (GI) cancer: An expanded dataset. Ann. Oncol. 2022, 33 (Suppl. 4), S370. [Google Scholar] [CrossRef]
  65. Cohen, R.; Pudlarz, T.; Delattre, J.F.; Colle, R.; André, T. Molecular Targets for the Treatment of Metastatic Colorectal Cancer. Cancers 2020, 12, 2350. [Google Scholar] [CrossRef]
  66. Forsythe, A.; Zhang, W.; Phillip Strauss, U.; Fellous, M.; Korei, M.; Keating, K. A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors. Ther. Adv. Med. Oncol. 2020, 12, 1758835920975613. [Google Scholar] [CrossRef] [PubMed]
  67. Torre, M.; Vasudevaraja, V.; Serrano, J.; DeLorenzo, M.; Malinowski, S.; Blandin, A.F.; Pages, M.; Ligon, A.H.; Dong, F.; Meredith, D.M.; et al. Molecular and clinicopathologic features of gliomas harboring NTRK fusions. Acta Neuropathol. Commun. 2020, 8, 107. [Google Scholar] [CrossRef] [PubMed]
  68. Gambella, A.; Senetta, R.; Collemi, G.; Vallero, S.G.; Monticelli, M.; Cofano, F.; Zeppa, P.; Garbossa, D.; Pellerino, A.; Rudà, R.; et al. NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target. Int. J. Mol. Sci. 2020, 21, 753. [Google Scholar] [CrossRef]
  69. Aldape, K.; Brindle, K.M.; Chesler, L.; Chopra, R.; Gajjar, A.; Gilbert, M.R.; Gottardo, N.; Gutmann, D.H.; Hargrave, D.; Holland, E.C.; et al. Challenges to curing primary brain tumours. Nat. Rev. Clin. Oncol. 2019, 16, 509–520. [Google Scholar] [CrossRef]
  70. LiVolsi, V.A.; Abrosimov, A.A.; Bogdanova, T.; Fadda, G.; Hunt, J.L.; Ito, M.; Rosai, J.; Thomas, G.A.; Williams, E.D. The Chernobyl thyroid cancer experience: Pathology. Clin. Oncol. 2011, 23, 261–267. [Google Scholar] [CrossRef]
  71. Cabanillas, M.E.; Lin, J.J.; Brose, M.S.; McDermott, R.S.; Almubarak, M.; Bauman, J.R.; Casanova, M.; Kummar, S.; Lee, S.H.; Leyvraz, S.; et al. Larotrectinib (laro) long-term efficacy and safety in patients (pts) with tropomyosin receptor kinase (TRK) fusion thyroid carcinoma (TC). J. Clin. Oncol. 2023, 41, 6091. [Google Scholar] [CrossRef]
  72. Taylor, J.; Pavlick, D.; Yoshimi, A.; Marcelus, C.; Chung, S.S.; Hechtman, J.F.; Benayed, R.; Cocco, E.; Durham, B.H.; Bitner, L.; et al. Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies. J. Clin. Investig. 2018, 128, 3819–3825. [Google Scholar] [CrossRef]
  73. Qin, K.; Hou, H.; Liang, Y.; Zhang, X. Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: A meta-analysis. BMC Cancer 2020, 20, 328. [Google Scholar] [CrossRef]
  74. Knezevich, S.R.; McFadden, D.E.; Tao, W.; Lim, J.F.; Sorensen, P.H. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat. Genet. 1998, 18, 184–187. [Google Scholar] [CrossRef]
  75. Agaram, N.P.; Zhang, L.; Sung, Y.S.; Chen, C.L.; Chung, C.T.; Antonescu, C.R.; Fletcher, C.D. Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors. Am. J. Surg. Pathol. 2016, 40, 1407–1416. [Google Scholar] [CrossRef]
  76. Kao, Y.C.; Fletcher, C.D.M.; Alaggio, R.; Wexler, L.; Zhang, L.; Sung, Y.S.; Orhan, D.; Chang, W.C.; Swanson, D.; Dickson, B.C.; et al. Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas: Expanding the Genetic Spectrum of Tumors with Overlapping Features with Infantile Fibrosarcoma. Am. J. Surg. Pathol. 2018, 42, 28–38. [Google Scholar] [CrossRef] [PubMed]
  77. Chiang, S.; Cotzia, P.; Hyman, D.M.; Drilon, A.; Tap, W.D.; Zhang, L.; Hechtman, J.F.; Frosina, D.; Jungbluth, A.A.; Murali, R.; et al. NTRK Fusions Define a Novel Uterine Sarcoma Subtype with Features of Fibrosarcoma. Am. J. Surg. Pathol. 2018, 42, 791–798. [Google Scholar] [CrossRef] [PubMed]
  78. Kojima, N.; Mori, T.; Motoi, T.; Kobayashi, E.; Yoshida, M.; Yatabe, Y.; Ichikawa, H.; Kawai, A.; Yonemori, K.; Antonescu, C.R.; et al. Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors with NTRK, BRAF, RAF1, or RET Fusions. Mod. Pathol. 2023, 36, 100083. [Google Scholar] [CrossRef] [PubMed]
  79. Xu, B.; Suurmeijer, A.J.H.; Agaram, N.P.; Antonescu, C.R. Head and Neck Mesenchymal Tumors with Kinase Fusions: A Report of 15 Cases with Emphasis on Wide Anatomic Distribution and Diverse Histologic Appearance. Am. J. Surg. Pathol. 2023, 47, 248–258. [Google Scholar] [CrossRef]
  80. Demetri, G.D.; Antonescu, C.R.; Bjerkehagen, B.; Bovée, J.V.M.G.; Boye, K.; Chacón, M.; Dei Tos, A.P.; Desai, J.; Fletcher, J.A.; Gelderblom, H.; et al. Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: Expert recommendations from the World Sarcoma Network. Ann. Oncol. 2020, 31, 1506–1517. [Google Scholar] [CrossRef] [PubMed]
  81. Kiuru, M.; Jungbluth, A.; Kutzner, H.; Wiesner, T.; Busam, K.J. Spitz Tumors: Comparison of Histological Features in Relationship to Immunohistochemical Staining for ALK and NTRK1. Int. J. Surg. Pathol. 2016, 24, 200–206. [Google Scholar] [CrossRef]
  82. Uguen, A. Spitz Tumors with NTRK1 Fusions: TRK-A and pan-TRK Immunohistochemistry as Ancillary Diagnostic Tools. Am. J. Surg. Pathol. 2019, 43, 1438–1439. [Google Scholar] [CrossRef] [PubMed]
  83. Yeh, I.; Tee, M.K.; Botton, T.; Shain, A.H.; Sparatta, A.J.; Gagnon, A.; Vemula, S.S.; Garrido, M.C.; Nakamaru, K.; Isoyama, T.; et al. NTRK3 kinase fusions in Spitz tumours. J. Pathol. 2016, 240, 282–290. [Google Scholar] [CrossRef]
  84. Yeh, I.; Busam, K.J.; McCalmont, T.H.; LeBoit, P.E.; Pissaloux, D.; Alberti, L.; de la Fouchardière, A.; Bastian, B.C. Filigree-like Rete Ridges, Lobulated Nests, Rosette-like Structures, and Exaggerated Maturation Characterize Spitz Tumors with NTRK1 Fusion. Am. J. Surg. Pathol. 2019, 43, 737–746. [Google Scholar] [CrossRef]
  85. Cappellesso, R.; Nozzoli, F.; Zito Marino, F.; Simi, S.; Castiglione, F.; De Giorgi, V.; Cota, C.; Senetta, R.; Scognamiglio, G.; Anniciello, A.M.; et al. NTRK Gene Fusion Detection in Atypical Spitz Tumors. Int. J. Mol. Sci. 2021, 22, 12332. [Google Scholar] [CrossRef]
  86. Forschner, A.; Forchhammer, S.; Bonzheim, I. NTRK gene fusions in melanoma: Detection, prevalence and potential therapeutic implications. J. Dtsch. Dermatol. Ges. 2020, 18, 1387–1392. [Google Scholar] [CrossRef]
  87. Lezcano, C.; Shoushtari, A.N.; Ariyan, C.; Hollmann, T.J.; Busam, K.J. Primary and Metastatic Melanoma with NTRK Fusions. Am. J. Surg. Pathol. 2018, 42, 1052–1058. [Google Scholar] [CrossRef]
  88. Wang, M.; Banik, I.; Shain, A.H.; Yeh, I.; Bastian, B.C. Integrated genomic analyses of acral and mucosal melanomas nominate novel driver genes. Genome Med. 2022, 14, 65. [Google Scholar] [CrossRef]
  89. Silvertown, J.D.; Lisle, C.; Semenuk, L.; Knapp, C.; Jaynes, J.; Berg, D.; Kaul, N.; Lachapelle, J.; Richardson, L.; Speevak, M.; et al. Prevalence of NTRK Fusions in Canadian Solid Tumour Cancer Patients. Mol. Diagn. Ther. 2023, 27, 87–103. [Google Scholar] [CrossRef]
  90. Laé, M.; Fréneaux, P.; Sastre-Garau, X.; Chouchane, O.; Sigal-Zafrani, B.; Vincent-Salomon, A. Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. Mod. Pathol. 2009, 22, 291–298. [Google Scholar] [CrossRef]
  91. Cao, Z.; Li, J.; Sun, L.; Xu, Z.; Ke, Y.; Shao, B.; Guo, Y.; Sun, Y. GISTs with NTRK Gene Fusions: A Clinicopathological, Immunophenotypic, and Molecular Study. Cancers 2022, 15, 105. [Google Scholar] [CrossRef]
Ijms 25 02366 g001
Figure 1. NTRK inhibitor mechanism of action. NTRK inhibitors block action through the NTRK receptor preventing downstream activation of phoshoinositide-3-kinase (PI3K), phospholipase C (PLC), and RAS pathways.
Figure 1. NTRK inhibitor mechanism of action. NTRK inhibitors block action through the NTRK receptor preventing downstream activation of phoshoinositide-3-kinase (PI3K), phospholipase C (PLC), and RAS pathways.
Ijms 25 02366 g001
Table 1. Timeline in year of NTRK gene and inhibitor therapy development.
Table 1. Timeline in year of NTRK gene and inhibitor therapy development.
1982Identification of NTRK as an oncogene in patient with colorectal carcinoma
1989Isolation of cDNA of the NTRK1 proto-oncogene
1997Gene mapping of NTRK1, NTRK2, and NTRK3 to human chromosomes, 1q22, 9q22, and 15q25 by FISH
2015First-generation NTRK inhibitors entered clinical trials
2017 Second-generation NTRK inhibitors entered clinical trials
2018FDA granted accelerated approval for larotrectinib for adult and pediatric patients with NTRK fusion-positive solid tumors
2019FDA granted accelerated approval for entrectinib for adult and pediatric patients with solid tumors with NTRK gene fusion without a known acquired resistance mutation
2020FDA granted Fast Track to repotrectinib in NTRK-positive advanced solid tumors
2021Phase 2 basket trial of taletrectinib for solid tumors with NTRK initiated
Table 2. Summarization of the clinical trials, findings, and side effects of NTRK inhibitors.
Table 2. Summarization of the clinical trials, findings, and side effects of NTRK inhibitors.
MedicationTarget GenesRelated TrialsFindingsSide Effects
Larotrectinib TRKA/B/CNCT02576431
NCT02122913
NCT02637687		ORR 75% (95% CI 68–81)
CR 22%
PR 109%
Stable 16%
PD 6%		18% Grade 3–4 treatment-related side effects
EntrectinibTRKA/B/C, ROS1, ALKALKA-372-001
STARTRK-1
STARTRK-2		ORR 57%
CR 7%
PR 50%
Stable 17%
PD 7%		10% weight gain, 12% anemia, 4% CNS manifestation
RepotrectinibTRKA/B/C, ROS1, ALKNCT03093116 (TRIDENT-1)ORR 41–62%Grade 1 CNS-related side effects
SelitrectinibTRKA/B/CNCT03215511
NCT03206931		N/AN/A
TaletrectinibTRKA/B/C, ALKNCT04395677N/AGI-related side effects—nausea, diarrhea, vomiting
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Theik, N.W.Y.; Muminovic, M.; Alvarez-Pinzon, A.M.; Shoreibah, A.; Hussein, A.M.; Raez, L.E. NTRK Therapy among Different Types of Cancers, Review and Future Perspectives. Int. J. Mol. Sci. 2024, 25, 2366. https://doi.org/10.3390/ijms25042366

AMA Style

Theik NWY, Muminovic M, Alvarez-Pinzon AM, Shoreibah A, Hussein AM, Raez LE. NTRK Therapy among Different Types of Cancers, Review and Future Perspectives. International Journal of Molecular Sciences. 2024; 25(4):2366. https://doi.org/10.3390/ijms25042366

Chicago/Turabian Style

Theik, Nyein Wint Yee, Meri Muminovic, Andres M. Alvarez-Pinzon, Ahmed Shoreibah, Atif M. Hussein, and Luis E. Raez. 2024. "NTRK Therapy among Different Types of Cancers, Review and Future Perspectives" International Journal of Molecular Sciences 25, no. 4: 2366. https://doi.org/10.3390/ijms25042366

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