Search

Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient‐derived LMNA::NTRK1‐rearranged soft‐tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK‐targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium‐throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1‐rearranged soft‐tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Purpose: Pathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC). Methods: A total of 184 TC patients with testing for NTRK gene fusions were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan–Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy. Results: 8/184 (4%) patients harbored NTRK gene fusions. Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 (n = 4) and NTRK3 (n = 2) gene fusions were treated with larotrectinib. Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy. All patients had morphologically progressive disease before treatment initiation. Objective response rate was 83%, including two complete remissions. Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0–57.4) and median OS was not reached (NR) (95% CI, NR). Adverse events were of grade 1–3. Conclusion: The prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile. [ABSTRACT FROM AUTHOR]

Background: This study analyzed real-world data from 2004 to 2023 to evaluate the toxicity profile of tyrosine receptor kinase (TRK) inhibitor therapy. Method: A retrospective analysis of US FDA Adverse Event Reporting System data was conducted to identify adverse events in patients receiving TRK inhibitor therapy. Result: Entrectinib demonstrated toxicities primarily in the cardiovascular and nervous systems, followed by the renal and urinary system. Common adverse effects included dizziness, renal impairment, constipation, heart failure and taste disorders. Larotrectinib induced adverse events mainly in the hepatobiliary and nervous systems, with peripheral neuropathy, myalgia, renal impairment and increased alanine aminotransferase commonly reported. Conclusion: Careful monitoring and supportive care strategies are essential for managing adverse events associated with TRK inhibitor therapy. [ABSTRACT FROM AUTHOR]

NTRK gene fusions have been identified in various tumors; some requiring aggressive therapy and sometimes new TRK inhibitors (TRKi). We aimed to describe a national, unselected, retrospective, multicenter cohort. Patients were identified through the French sarcoma diagnostic laboratory at Institut Curie through samples analyzed by RT-qPCR or whole-transcriptome sequencing. From 2001 to 2019, 65 NTRK fusion tumors were identified within 2120 analyses (3.1%): 58 by RNA sequencing (including 20 after RT-qPCR analysis) and 7 exclusively by RT-qPCR. Of the 61 patients identified, 37 patients had infantile soft tissue or kidney fibrosarcomas (IFS), 15 other mesenchymal (Other-MT) and nine central nervous system (CNS) tumors. They encompassed 14 different tumor types with variable behaviors. Overall, 53 patients had surgery (3 mutilating), 38 chemotherapy (20 alkylating agents/anthracycline), 11 radiotherapy, two 'observation strategy' and 13 received TRKi. After a median follow-up of 61.0 months [range, 2.5–226.0], 10 patients died. Five-year overall survival is, respectively, 91.9% [95%CI, 83.5–100.0], 61.1% [95%CI, 34.2–100.0] and 64.8% [95%CI, 39.3–100.0] for IFS, Other-MT, and CNS groups. NTRK-fusion positive tumors are rare but detection is improved through RNA sequencing. TRKi could be considered at diagnosis for CNS NTRK-fusion positive tumors, some IFS, and Other-MT. Not adapted. [ABSTRACT FROM AUTHOR]

The occurrence of neurotrophic tyrosine receptor kinase (NTRK) gene fusions in a wide range of tumor types presents an attractive opportunity for using a tropomyosin receptor kinase (TRK) inhibitor as cancer therapy. Recent clinical studies have demonstrated highly efficacious outcomes associated with the use of TRK inhibitors, such as larotrectinib and entrectinib in NTRK fusion‐bearing cancers, in both adult and pediatric populations. While NTRK gene fusions are commonly found in some uncommon adult and pediatric malignancies, they are also found, albeit rarely, in a wide range of more common malignancies. The potential value of testing for NTRK gene fusions in practically all advanced malignancies is underpinned by the remarkable therapeutic outcomes that TRK inhibitors offer. This requirement presents practical and financial challenges in real‐world oncological practice. Furthermore, different testing platforms exist to detect NTRK gene fusions, each with its advantages and disadvantages. It is, therefore, imperative to develop strategies for NTRK gene fusion testing in an attempt to optimize the use of limited tissue specimen and financial resources, and to minimize the turnaround time. A multidisciplinary task force of Singapore medical experts in both public and private sectors was convened in late 2020 to propose testing algorithms for adult colorectal tumors, sarcomas, non‐small cell lung cancer, and pediatric cancers, with particular adaptation to the Singapore oncological practice. The recommendations presented here highlight the heterogeneity of NTRK‐fusion positive cancers, and emphasize the need to customize the testing methods to each tumor type to optimize the workflow. [ABSTRACT FROM AUTHOR]

Protein kinases play crucial roles in many cellular signaling processes, making them become important targets for drug discovery. But drug resistance mediated by mutation puts a barrier to the therapeutic effect of kinase inhibitors. Fragment-based drug discovery has been successfully applied to overcome such resistance. However, the complicate kinase-inhibitor fragment interaction and fragment-to-lead process seriously limit the efficiency of kinase inhibitor discovery against resistance caused by mutation. Here, we constructed a comprehensive web platform KinaFrag for the fragment-based kinase inhibitor discovery to overcome resistance. The kinase-inhibitor fragment space was investigated from 7783 crystal kinase-inhibitor fragment complexes, and the structural requirements of kinase subpockets were analyzed. The core fragment-based virtual screening workflow towards specific subpockets was developed to generate new kinase inhibitors. A series of tropomyosin receptor kinase (TRK) inhibitors were designed, and the most potent compound YT9 exhibits up to 70-fold activity improvement than marketed drugs larotrectinib and selitrectinib against G595R, G667C and F589L mutations of TRKA. YT9 shows promising antiproliferative against tumor cells in vitro and effectively inhibits tumor growth in vivo for wild type TRK and TRK mutants. Our results illustrate the great potential of KinaFrag in the kinase inhibitor discovery to combat resistance mediated by mutation. KinaFrag is freely available at http://chemyang.ccnu.edu.cn/ccb/database/KinaFrag/. [ABSTRACT FROM AUTHOR]

Secretory carcinoma of the thyroid gland is histologically and genetically similar to its mammary and salivary gland counterparts. Unlike differentiated thyroid carcinomas of follicular cell origin, thyroid SC is not a thyroglobulin-producing tumor and would not be amenable to radioactive iodine therapy. Instead, these carcinomas may respond to targeted therapy with TRK inhibitors, which further emphasizes the importance of their recognition among morphologically similar thyroid entities. Based on eleven cases reported to date, most primary thyroid SC tend to present as locally advanced malignancies and are characterized by frequent recurrences and long-term survival. High-grade histologic features, increased mitotic count and necrosis have been described but their impact on clinical course and outcome remains unclear. We hereby report the case of a primary SC with high-grade features arising in the thyroid of a 49-year-old man, who was treated with Larotrectinib for his second recurrence. The patient achieved a durable response that lasted for 18 months but then he continued to progress and died of disease 181 months after the diagnosis. [ABSTRACT FROM AUTHOR]

In May 2020, larotrectinib (Vitrakvi®) was approved as the first tumor-agnostic agent in Switzerland for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. While in certain types of tumors an NTRK gene fusion is often detectable, it is rare in some other types. As the detection of NTRK gene fusion opens up new treatment options for patients, it is vital to ensure that the detection methods and diagnostic algorithms in pathology institutes are optimized and of high quality. Detection can be performed by immunohistochemistry, next-generation sequencing or by fluorescence in situ hybridization. This review will discuss diagnostic algorithms based on underlying pathology that can be recommended for the detection of NTRK gene fusions in Switzerland.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusion has been identified as an oncogenic driver of various solid tumors, and it is rare in non-smalll cell lung cancer (NSCLC) with a frequency of approximately less than 1%. Next-generation sequencing (NGS) is of priority for detecting NTRK fusions, especially RNA-based NGS. Currently, the tropomyosin receptor kinase (TRK) inhibitors have shown promising efficacy and well tolerance in patients with NTRK fusion-positive solid tumors, regardless of tumor histology. The first-generation TRK inhibitors (larotrectinib and entrectinib) are recommended as the first-line treatment for locally advanced or metastatic NSCLC patients with positive NTRK fusion. However, TRK inhibitor resistance can eventually occur due to on-target or off-target mechanisms. Further studies are under investigation to overcome resistance and improve survival. Interestingly, NTRK fusion might be the mechanism of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in NSCLC patients with EGFR mutation. Regarding immunotherapy, the efficacy of immune checkpoint inhibitors in NSCLC patients harboring NTRK fusion has yet to be well described. In this review, we elucidate the function of NTRK genes, summarize the diagnostic techniques for NTRK fusions, and present clinical data for TRK inhibitors; we also discuss potential mechanisms of resistance to TRK inhibitors. [ABSTRACT FROM AUTHOR]

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusion has been identified as an oncogenic driver of various solid tumors, and it is rare in non-smalll cell lung cancer (NSCLC) with a frequency of approximately less than 1%. Next-generation sequencing (NGS) is of priority for detecting NTRK fusions, especially RNA-based NGS. Currently, the tropomyosin receptor kinase (TRK) inhibitors have shown promising efficacy and well tolerance in patients with NTRK fusion-positive solid tumors, regardless of tumor histology. The first-generation TRK inhibitors (larotrectinib and entrectinib) are recommended as the first-line treatment for locally advanced or metastatic NSCLC patients with positive NTRK fusion. However, TRK inhibitor resistance can eventually occur due to on-target or off-target mechanisms. Further studies are under investigation to overcome resistance and improve survival. Interestingly, NTRK fusion might be the mechanism of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in NSCLC patients with EGFR mutation. Regarding immunotherapy, the efficacy of immune checkpoint inhibitors in NSCLC patients harboring NTRK fusion has yet to be well described. In this review, we elucidate the function of NTRK genes, summarize the diagnostic techniques for NTRK fusions, and present clinical data for TRK inhibitors; we also discuss potential mechanisms of resistance to TRK inhibitors.

Abstract Larotrectinib is an orally administered drug and the first and only selective pan-tropomyosin receptor kinase (TRK) inhibitor in clinical development to treat cancer patients harboring a neurotrophic receptor tyrosine kinase gene fusion. In this study, an analytical method to quantify the TRK inhibitor in mouse and human plasma was developed and validated using LC-MS/MS following protein precipitation with acetonitrile. Larotrectinib and an internal standard (carbamazepine) were separated from endogenous substances using an Xterra C18 column with acetonitrile containing 0.1% formic acid as the mobile phase. The ions m/z 429.8 → 342.8 for larotrectinib and m/z 237.0 → 194.0 for carbamazepine detected in multiple reaction monitoring mode were used for the quantitation. The detector response of larotrectinib was linear within the concentration range 5–10,000 ng/mL with a correlation coefficient (r 2) of not less than 0.999. The intra- and inter-day precision and accuracy were less than 10.48% and within − 8.99%, respectively, in mouse and human plasma. Larotrectinib was stable under various storage and handling conditions, and no significant matrix effect was observed in both mouse and human plasma. Finally, the assay was successfully applied to the pharmacokinetic study of larotrectinib after its intravenous and oral administration to mice.

Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK-targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium-throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1-rearranged soft-tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Patients with infantile fibrosarcoma (IFS) have shown strong and long-lasting responses to larotrectinib, a tropomyosin receptor kinase inhibitor (TRKi), in single-arm clinical trials. Conventional chemotherapy has also shown important efficacy. But, until now, no comparative data exist. This study aims to assess the therapeutic benefit of larotrectinib over the current standard of care (SOC) of chemotherapy in paediatric patients with locally advanced or metastatic IFS., Patients and Methods: EPI VITRAKVI is a retrospective, observational, externally controlled study (NCT05236257). Data of patients aged ≤21 years with locally advanced or metastatic IFS treated with larotrectinib in the phase I/II SCOUT trial (NCT02637687) were compared with those of an external historical control group (data of Institut Curie and Cooperative Weichteilsarkom Studiengruppe) treated with a chemotherapy-based regimen. Between-group differences were assessed after balancing groups using inverse probability of treatment weighting (IPTW)., Results: In total, 93 patients were compared, 51 in the larotrectinib arm and 42 in the external control arm. After therapy, 4 patients (7.8%) in the larotrectinib group had a medical treatment failure event [start of new systemic treatment (2 cases), mutilating surgery (2 cases)] versus 15 (35.7%) in the external control group [start of new systemic treatment (6 cases), mutilating surgery (5 cases), radiation therapy (2 cases), and death (2 cases)]. Larotrectinib was associated with an 80% reduced likelihood of encountering a medical treatment failure event, when compared to the external control group (weighted and stratified hazard ratio 0.20, 95% confidence interval 0.06-0.63, P = 0.0060). These results were confirmed by sensitivity analyses, including exact matching, and subgroup analyses for number of lines of treatment., Conclusions: Treatment with larotrectinib reduced the need of subsequent therapies compared to SOC with chemotherapy in children with locally advanced or metastatic IFS, regardless of the line of treatment., Competing Interests: Disclosure SKK, MF, and MK are Bayer employees. DO had a consultant activity for Bayer and Roche and is an Independent Data Monitoring Committee (IDMC) member for a Lilly product and is a consultant for Novartis Pharma France and Eusapharm. MC had a consultant activity for Bayer. MSS had advisory activity for Bayer, Roche, and Sobi. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This case report reviews the case of a 13-year-old patient who presented with a 9 cm NTRK1-rearranged cervical sarcoma with fibrosarcoma like morphology. At presentation the lesion filled her vagina and pelvis and any attempt at surgical removal would have been morbid and led to loss of fertility. These neoplasms are extremely rare with 18 cases of the uterine cervix reported in the literature, none of which have occurred in a paediatric patient, and none of whom have received neo-adjuvant therapy prior to excision. Based upon evidence that has shown good tolerability and responses of paediatric NTRK fusion-positive solid tumours to TRK inhibitors, both in the neo-adjuvant and upfront setting, this patient was managed with neo-adjuvant entrectinib. Following a dramatic reduction in tumour size confirmed by imaging, she underwent conservative fertility sparing surgery with final histopathology showing no residual disease.

A Belgian ring trial for pan-TRK immunohistochemistry (IHC) staining was organised to harmonise pan-TRK IHC staining protocols and interpretation. As a reference method, the VENTANA pan-TRK Assay (clone EPR17341) on the Benchmark Ultra platform was selected. Six samples were selected: 2 negative, 2 fusion positive and 2 samples with wild-type endogenous TRK expression. Each participating laboratory stained the slides using their routine pan-TRK IHC and reported their results. In addition, they were asked to return one TRK-stained slide from each case. The coordinating lab evaluated these slides, compared them with the reference method and scored them. Two clones were used during the ring trial: A7H6R (Cell Signaling) and EPR17341 (Abcam/Ventana). Seven protocols achieved a sufficient performance mark, and three labs were advised to further optimise the protocol. Interpretation of pan-TRK IHC proved to be challenging in cases with physiological TRK expression. In addition, depending on the NTRK fusion partner, the staining can vary strongly in both intensity and staining pattern. Labs using the Ventana ready-to-use system based on the EPR17341 clone and using the recommended protocol settings scored best. However, given some small optimisation, all labs scored well on the technical staining and the succeeding evaluation. [ABSTRACT FROM AUTHOR]

Introduction: The Trk family proteins are membrane-bound kinases predominantly expressed in neuronal tissues. Activated by neurotrophins, they regulate critical cellular processes through downstream signaling pathways. Dysregulation of Trk signaling can drive a range of diseases, making the design and study of Trk inhibitors a vital area of research. This review explores recent advances in the development of type II and III Trk inhibitors, with implications for various therapeutic applications., Areas Covered: Patents covering type II and III inhibitors targeting the Trk family are discussed as a complement of the previous review, Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update . Relevant patents were identified using the Web of Science database, Google, and Google Patents., Expert Opinion: While type II and III Trk inhibitor development has advanced more gradually compared to their type I counterparts, they hold significant promise in overcoming resistance mutations and achieving enhanced subtype selectivity - a critical factor in reducing adverse effects associated with pan-Trk inhibition. Recent interdisciplinary endeavors have marked substantial progress in the design of subtype selective Trk inhibitors, with impressive success heralded by the type III inhibitors. Notably, the emergence of mutant-selective Trk inhibitors introduces an intriguing dimension to the field, offering precise treatment possibilities.

Larotrectinib is an orally administered drug and the first and only selective pan-tropomyosin receptor kinase (TRK) inhibitor in clinical development to treat cancer patients harboring a neurotrophic receptor tyrosine kinase gene fusion. In this study, an analytical method to quantify the TRK inhibitor in mouse and human plasma was developed and validated using LC-MS/MS following protein precipitation with acetonitrile. Larotrectinib and an internal standard (carbamazepine) were separated from endogenous substances using an Xterra C18 column with acetonitrile containing 0.1% formic acid as the mobile phase. The ions m/z 429.8 → 342.8 for larotrectinib and m/z 237.0 → 194.0 for carbamazepine detected in multiple reaction monitoring mode were used for the quantitation. The detector response of larotrectinib was linear within the concentration range 5–10,000 ng/mL with a correlation coefficient (r2) of not less than 0.999. The intra- and inter-day precision and accuracy were less than 10.48% and within − 8.99%, respectively, in mouse and human plasma. Larotrectinib was stable under various storage and handling conditions, and no significant matrix effect was observed in both mouse and human plasma. Finally, the assay was successfully applied to the pharmacokinetic study of larotrectinib after its intravenous and oral administration to mice. [ABSTRACT FROM AUTHOR]

Introduction: Detecting oncogenic drivers across multiple cancers has brought about a shift toward a more targeted therapeutic approach. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are genomic rearrangements containing the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain contributed by another gene, generating fusion proteins, which are oncogenic drivers, targetable with TRK inhibitors. Larotrectinib is a first-in-class TRK inhibitor, granted accelerated FDA approval for treating TRK fusion cancer. This breakthrough indication across cancer subtypes and ages, from infancy through adulthood, highlights the need to understand the heterogeneous patient population and cancer types studied in larotrectinib clinical trials. Areas covered: We provide a narrative review of preclinical, pharmacokinetic, efficacy, and safety data for larotrectinib from three clinical trials that led to regulatory approval. Expert opinion: Larotrectinib elicits impressive responses in most patients with TRK fusion cancer, regardless of tumor type and age. Treatment is well tolerated with a low rate of treatment-emergent grade 3–4 adverse events, dose reductions and discontinuations due to adverse events, and recent findings indicate patient-reported improvement in quality of life. This highlights the importance of early testing for NTRK gene fusions in cancers that may harbor them, even if rare. [ABSTRACT FROM AUTHOR]

Introduction: TRK fusions occur across a wide range of cancers in children and adults. These fusions drive constitutive expression and ligand-independent activation of the TRK kinase and are oncogenic. Larotrectinib is the first highly potent and selective small molecule ATP competitive inhibitor of all three TRK kinases to enter clinical development. Areas covered: This review covers the current preclinical and clinical evidence for TRK inhibitors for TRK fusion cancers, focusing on larotrectinib. Expert commentary: Larotrectinib has demonstrated a remarkable 75% centrally confirmed objective response rate in patients with TRK fusion cancers in phase 1 and phase 2 clinical trials with generally mild side effects. Responses appear independent of the patient's age, underlying histology, and specific fusion partner and are durable in many patients. Larotrectinib is likely to be the first FDA-approved histology-agnostic molecularly targeted therapy. The evolving role of molecular profiling of advanced cancers is discussed. [ABSTRACT FROM AUTHOR]

Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dosedependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common endocrine cancer. Neurotrophic tyrosine receptor kinase (NTRK) fusions are oncogenic drivers in multiple solid tumors, including thyroid cancer. NTRK fusion thyroid cancer has unique pathological features such as mixed structure, multiple nodes, lymph node metastasis, and a background of chronic lymphocytic thyroiditis. Currently, RNA-based next-generation sequencing is the gold standard for the detection of NTRK fusions. Tropomyosin receptor kinase inhibitors have shown promising efficacy in patients with NTRK fusion-positive thyroid cancer. Efforts to overcome acquired drug resistance are the focus of research concerning next-generation TRK inhibitors. However, there are no authoritative recommendations or standardized procedures for the diagnosis and treatment of NTRK fusions in thyroid cancer. This review discusses current research progress regarding NTRK fusion-positive thyroid cancer, summarizes the clinicopathological features of the disease, and outlines the current statuses of NTRK fusion detection and targeted therapeutic agents. [Display omitted] ● NTRK fusions are oncogenic drivers in thyroid cancer. ● NTRK fusion-positive thyroid cancer has unique pathological features. ● TRK inhibitors effectively treat NTRK fusion-positive thyroid cancer. [ABSTRACT FROM AUTHOR]

Introduction: Oncogenic NTRK fusions have been found in multiple cancer types affecting adults and/or children, including rare tumors with pathognomonic fusions and common cancers in which fusions are rare. The tropomyosin receptor kinase inhibitors (TRKi) larotrectinib and entrectinib are among the first agents with tissue agnostic FDA approvals for cancer treatment, and additional TRKi are undergoing development. As experience with TRKi grow, novel mechanisms of resistance and on/off target side effects have become increasingly important considerations., Areas Covered: Authors reviewed literature published through July 2023 on platforms such as PubMed, clinicaltrials.gov, and manufacturer/FDA drug labels, focusing on the development of TRKi, native functions of TRK, phenotype of congenital TRK aberrancies, efficacy, and safety profile of TRKi in clinical trials and investigator reports, and on/off target adverse effects associated with TRKi (Appendix A)., Expert Opinion: TRKi have histology-agnostic activity against tumors with NTRK gene fusions. TRKi are generally well tolerated with a side effect profile that compares favorably to cytotoxic chemotherapy. There are numerous ongoing studies investigating TRKi as frontline, adjuvant, and salvage therapy. It will be critical to continue to gather long-term safety data on the use of these agents, particularly in children.

Introduction: Trk inhibitors are significant in the realm of personalized medicine as they target specific genetic alterations, such as NTRK gene fusions, leading to improved treatment outcomes for cancer patients. By tailoring the treatment to the genetic characteristics of the tumor rather than the tumor type, Trk inhibitors offer the potential for more effective and precise therapies, resulting in enhanced response rates and prolonged survival for patients with NTRK fusion-positive cancers., Areas Covered: Patents covering type I inhibitors targeting the Trk family are discussed, building upon our prior review series on Trk inhibitors. Relevant patents were identified through the Web of Science database, Google, and Google Patents., Expert Opinion: The field of Trk inhibitors has evolved significantly, as reflected in the current patent literature, which emphasizes the selective structural refinement of clinical champions. Efforts now concentrate on enhancing efficacy against on-target resistance mechanisms, with modifications made to improve potency, reduce toxicity, and enhance pharmacokinetics. Combination therapies show potential to address off-target resistance mechanisms and improve treatment outcomes. Challenges remain in accurately diagnosing NTRK gene alterations and integrating screening into routine clinical practice. Trk inhibitors have surpassed their conventional role of inhibition and are now seeing new applications in radiopharmaceutical development and as molecular targeting agents.

We report two cases of pediatric mammary-analog secretory carcinoma (MASC), a male operated on at age 8 and a female operated on at 12, who are in remission 2 years after surgery. The diagnosis of MASC was challenging and established by identifying the ETV6::NTRK3 fusion transcript in both cases. Given the excellent results of TRK inhibitor treatments in adult MASC and pediatric tumors expressing an ETV6::NTRK3 fusion, they should probably be prescribed as first-line treatment in cases requiring surgery with foreseeable serious sequelae or metastatic disease., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Apart for infantile fibrosarcoma (IFS), very little is known about NTRK-rearranged mesenchymal tumors (NMTs). The objective of this study is to describe the distribution, characteristics, natural history, and prognosis of NMT., Patients and Methods: This study was carried out as a translational research program, retrospectively from a cohort of 500 soft tissue sarcoma (STS; excluding IFS) and prospectively both in routine practice and from the RNASARC molecular screening program (N = 188; NCT03375437)., Results: Using RNA-sequencing, NTRK fusion was detected in 16 patient tumors diagnosed as STS: 8 samples of sarcoma with simple genomics (4 NTRK-rearranged spindle cell neoplasm, 3 ALK/ROS wild-type inflammatory myofibroblastic tumor, and 1 quadruple Wild-type gastrointestinal stromal tumor) and 8 samples of sarcomas with complex genomics (dedifferentiated liposarcoma, intimal sarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma, high-grade uterine sarcoma, malignant peripheral nerve sheath tumor). Among the eight patients with simple genomics, four were treated with tyrosine receptor kinase inhibitor (TRKi) at different stages of the disease and all benefited from the treatment, including one complete response. Among the eight other patients, six evolved with metastatic spreading and the median metastatic survival was 21.9 months, as classically reported in these tumor types. Two of them received a first-generation TRKi without objective response., Conclusions: Our study confirms low frequency and histotype diversity of NTRK fusion in STS. While the activity of TRKi in simple genomics NMT is confirmed, our clinical data encourage subsequent studies focusing on the biological relevance of NTRK fusions in sarcomas with complex genomics together with the efficacy of TRKi in this population., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Enzymatic kinase assays and docking simulation studies have shown that the natural product wrightiadione displays inhibitory activity toward TrkA and PLK3. In this study, the template of wrightiadione served as a starting point for Trk inhibitor development campaigns. Molecular simulation provided structural insights for the design of derivatives that were efficiently generated by our recently developed 3-step tandem synthetic approach, resulting in the discovery of compound 2h with biochemical potency at the single-digit micromolar level. [ABSTRACT FROM AUTHOR]

Mutation-induced resistance to targeted drug treatment poses a serious threat to successful chemotherapy. Multiple mutations underlying drug resistance remain a largely unsolved scientific issue. Tropomyosin receptor kinases (TRKs) are promising therapeutic targets for several malignant human cancers, but they have become less effective due to multiple resistance mutations. Thus, TRKs are representative cases to explore the problem of multiple resistance mutations. Here, we proposed a conformational adjustment strategy of drug design to overcome multiple resistance mutations in cancer treatments. A representative inhibitor, TIY-7, exhibited remarkable inhibitory activity against five TRK mutants, showing an IC 50 value of 1.1 nM against the most severe mutant TRKA-G595R. Moreover, it displayed superior tumor growth inhibitory activity compared with the clinically used drug selitrectinib. These results validated our strategy to design a new inhibitor structure to overcome multiple resistance mutations. [Display omitted] • TRK is a promising drug target for NTRK gene fusion cancers. • Multiple resistance mutations are a great challenge for cancer therapy. • A novel inhibitor TIY-7 was designed and tested, showing high inhibitory activity. • In vivo study revealed the greater anticancer potency of TIY-7 than selitrectinib. [ABSTRACT FROM AUTHOR]

Fusions of NTRK (neurotrophic tyrosine receptor kinase) genes with 5' partner genes can result in the expression of chimeric proteins that drive oncogenesis through ligand-independent kinase activation. Despite variable frequencies of NTRK fusions in different tumor types, the fact that they are common to a wide range of cancers raises the possibility of developing tumor-agnostic treatments specifically targeting NTRK fusion products, irrespective of tumor type. The first-generation Trk (tropomyosin receptor kinase) inhibitor, larotrectinib, was the first tumor-agnostic treatment of NTRK fusion-positive cancers in adults and children, to be approved in the European Union. This consensus, developed by a Belgian multidisciplinary expert panel, aims to highlight the unmet medical need associated to NTRK fusion-driven cancer treatment and, based on current knowledge of NTRK fusions and larotrectinib treatment outcome and safety, provide comprehensive guidance to oncologists regarding NTRK fusion-driven cancer diagnostics and the best use of larotrectinib in real-world clinical settings., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Mammary analog secretory carcinoma (MASC), or secretory carcinoma of the thyroid is an extremely rare disease harboring ETV6-NTRK3 gene fusion with TRK activation. Here we report the twelfth case of MASC of the thyroid worldwide. A 36-year-old female was diagnosed with poor-differentiated thyroid carcinoma (PDTC). Pathology consultant and immunochemical workups showed the tumor cells were negative for TTF1, TG, PAX8, positive for S100, Vimentin, GATA-3, and focally positive for mammaglobin. Fluorescence in situ hybridization (FISH) assay using a dual-color break-apart probe showed ETV6 translocation t(12p13) (ETV6) was present and established the diagnosis of MASC. Next-generation sequencing (NGS) of a 47-gene panel identified exon 1-5 of ETV6 gene were fused with exons 15-19 of NTRK3 gene. The patient experienced three loco-regional recurrences within 12 months and eventually developed inoperable local disease as well as bilateral lung metastasis. She is currently receiving anti-TRK treatment with a follow-up time of 33 months. A literature review of MASC in the thyroid was also conducted. [ABSTRACT FROM AUTHOR]

A Belgian ring trial for pan-TRK immunohistochemistry (IHC) staining was organised to harmonise pan-TRK IHC staining protocols and interpretation. As a reference method, the VENTANA pan-TRK Assay (clone EPR17341) on the Benchmark Ultra platform was selected. Six samples were selected: 2 negative, 2 fusion positive and 2 samples with wild-type endogenous TRK expression. Each participating laboratory stained the slides using their routine pan-TRK IHC and reported their results. In addition, they were asked to return one TRK-stained slide from each case. The coordinating lab evaluated these slides, compared them with the reference method and scored them. Two clones were used during the ring trial: A7H6R (Cell Signaling) and EPR17341 (Abcam/Ventana). Seven protocols achieved a sufficient performance mark, and three labs were advised to further optimise the protocol. Interpretation of pan-TRK IHC proved to be challenging in cases with physiological TRK expression. In addition, depending on the NTRK fusion partner, the staining can vary strongly in both intensity and staining pattern. Labs using the Ventana ready-to-use system based on the EPR17341 clone and using the recommended protocol settings scored best. However, given some small optimisation, all labs scored well on the technical staining and the succeeding evaluation.

Introduction : Tropomyosin receptor kinases (Trks) control processes in the fields of growth, survival, and differentiation of neuronal processes. They also play a crucial role in neurodegenerative diseases as well as different types of cancer. Interest in developing Trk inhibitors to target NTRK fusion-driven cancers has escalated in the last decade, leading to the FDA approval of the pan-Trk inhibitors entrectinib and larotrectinib. The development of next-generation inhibitors that overcome resistance mutations arising from treatment with these first generation inhibitors has been the focus in recent years. Area covered : In this updated patent review for 2016-2019, patents covering inhibitors targeting the Trk family are discussed as a continuation of the previous reviews, Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Parts 1 & 2 . The status of Trk inhibitors in clinical trials is also evaluated. For the identification of relevant patents and clinical trials, Web of Science, Google, Google Patents, and patent referencing were used. Expert opinion : The FDA approval of larotrectinib and entrectinib is a prime example of how basket clinical trial design targeting oncogenic drivers, regardless of tumor histology, is a viable approach to drug discovery and embodies the shift toward personalized medicine.

The neurotrophic tyrosine receptor kinases (NTRK) play an important role in the development and function of the nervous system. Fusions involving NTRK and a wide range of genes that act as fusion partners are oncogenic and activate well-known signal transduction pathways like the MAPK-ERK pathway. NTRK fusions occur in many very different tumor entities in children and youth as well as in adults. There are a few tumors like secretory breast cancer and congenital fibrosarcoma for which NTRK fusions are pathognomonic. At the same time there a large number of tumors in which NTRK fusions occur in very rare frequency (e.g., lung cancer). TRK inhibitors offer now the possibility to use NTRK fusion as antitumorigenic targets in a tumor agnostic fashion regardless of the basic histology. It is the task of modern pathology to identify such targetable fusions in a highly effective and efficient manner. [ABSTRACT FROM AUTHOR]

Mesoblastic nephroma is the most frequent renal tumor in newborns and young infants, and the cellular type is characterized by an ETV6-NTRK fusion, which constitutively activates the tropomyosin-related kinase (TRK) signaling pathway. Larotrectinib is a highly selective TRK inhibitor with activity in adult and pediatric patients who have TRK fusions. We present a rare case of a patient with mesoblastic nephroma metastatic to bone who had a dramatic response to larotrectinib., (© 2018 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors., (© 2018 Society for Endocrinology.)

We previously reported that brain-derived neurotrophic factor (BDNF)/neurotrophic receptor tyrosine kinase 2 (NTRK2/TRKB) signaling contributes to induction of malignant phenotype of gallbladder cancer (GBC). Recently, pan-TRK inhibitors have been evaluated and their dramatic clinical activity is being shown for a variety of cancer types harboring an NTRK rearrangement in phase I trials. ONO-7579 is an oral pan-TRK inhibitor currently under investigation in phase I/II clinical trial for TRK-rearranged solid tumors. In this study, we evaluated the anticancer effect of ONO-7579 using GBC cells with or without KRAS mutant, NOZ, TYGBK-1. Our study showed that ONO-7579 had a suppressive effect on GBC proliferation in TYGBK-1, and on invasive potential and vascular endothelial growth factor expression in TYGBK-1 and NOZ. Our data indicated that ONO-7579 could be a promising treatment option for patients with GBC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)