NTRK Fusions Research Articles

CNSC-10. WHEN GOOD THINGS GO OFF TRK: THE INTERSECTION OF NEUROSCIENCE & ONCOLOGY

Abstract How and why do processes and molecular players that were once an integral part of normal neurodevelopment go awry in pathological conditions, such as cancer? Embryogenesis, and neurodevelopment in particular, comprise an elegant and well-orchestrated series of tightly regulated events, culminating in an organized and highly functioning organism. Cancer, on the other hand, can often be viewed as an uncontrolled, unrestrained, genetically chaotic disease, lacking the precise spatial and temporal rigidity associated with normal development. While appearing to be on opposite sides of the organizational spectrum, the similarities between early neurodevelopment and oncogenesis are numerous. The link between developmental signaling and cancer initiation, maintenance, and metastasis has long been known for several members of the Wnt, Hedgehog, and Notch pathways and years of gene-level analyses have provided a wealth of knowledge and mechanistic insight. As advances in next generation sequencing allow for deeper characterization of genetic programs, it is increasingly possible to explore various isoforms of cancer associated genes. It is widely known that neurotrophins and their receptors (TrkA, TrkB, TrkC) are instrumental for neurodevelopment and that they remain critical for proper neuronal functioning throughout life. Our work highlights a previously unidentified role for an alternatively spliced neurotrophin receptor in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in humans and mice. This specific isoform, TrkB.T1, is the predominant NTRK2 isoform across embryonic organogenesis, and forced overexpression of this embryonic pattern causes multiple solid and nonsolid tumors in mice. TrkB.T1 also emerges as the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring various NTRK fusions. This work hopes to address the fundamental question of how neurodevelopmental processes can go awry in cancer, while seeking to better characterize the role of TRKs, in normal developmental processes and oncogenesis.

Redefining pancreatic cancer management with tumor-agnostic precision medicine.

Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into shared biomarkers. In the case of pancreatic cancer, the prevalence of the KRAS gene mutation is noteworthy. However, there exist other actionable alterations, such as BRCA1/2 mutations and fusion genes (BRAF, FGFR2, RET, NTRK, NRG1, and ALK), which present potential targets for therapy. Notably, tumor-agnostic drugs have demonstrated efficacy in specific subsets of pancreatic cancer patients who harbor these genetic alterations. Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers. Moreover, targeted therapies for BRAF V600, RET fusions, and HER2/neu overexpression have displayed promising results in specific subsets of pancreatic cancer patients. Emerging targets like NRG fusions, FGFR2 fusions, TP53 mutations, and KRAS G12C mutations present potential avenues for targeted therapy. Tumor-agnostic therapies have the potential to revolutionize pancreatic cancer treatment by focusing on specific genetic alterations. It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

Clinically aggressive follicular cell-derived thyroid carcinoma: A comprehensive series with histomolecular characterization and discovery of novel gene fusions

Thyroid cancer rates are increasing, mostly with a good prognosis and less than 2 % of cases are more aggressive. Recent efforts focus on understanding molecular events predicting tumor aggressiveness and treatment targets in advanced thyroid cancer. This study concerned 57 patients with aggressive metastatic, and/or radioiodine-refractory thyroid carcinomas, excluding anaplastic cases. Molecular profiling, including next-generation sequencing and RNA sequencing, was conducted to dissect the complex molecular landscape of these aggressive tumors. Histopathological analysis indicated that papillary carcinomas and high-grade thyroid carcinomas were predominant. The molecular analysis revealed a spectrum of mutations, with prevalent occurrences of BRAF V600E, TERT promoter, and RAS mutations. RNA sequencing identified ten gene fusions, such as NTRK and RET fusions. Three novel fusions were discovered: UGGT1::TERT, BTBD9::TERT, and TG::IGF1R, potentially driving aggressive behavior. UGGT1::TERT was linked to radioiodine-refractory tall cell PTC, BTBD9::TERT to high-grade follicular PTC, and TG::IGF1R to oncocytic carcinoma. These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.

LMNA::NTRK1 and PRDX1::NTRK1 Atypical Spitz Tumor: A Report of Two Additional Cases With Histological, Immunohistochemical, and Molecular Insights.

Over the past decade, advancements in molecular biology have contributed to changes in the diagnostic classification of Spitz neoplasms, including Spitz nevi, atypical Spitz tumors, and Spitz melanomas. The recent World Health Organization classification of skin tumors identifies fusion kinases, including NTRK1, NTRK2, and NTRK3, as critical drivers of these lesions. New fusion genes have continued to expand the spectrum of known molecular alterations, particularly within the category of Spitz NTRK-rearranged lesions. We present 2 new cases of NTRK-rearranged Spitz lesions: an atypical Spitz tumor with common LMNA::NTRK1 fusion and an atypical Spitz tumor with a rare PRDX1::NTRK1 fusion. Clinical, histopathological, immunohistochemical, and molecular analyses were performed to diagnose these patients. This report adds to the growing body of knowledge on NTRK-rearranged Spitz lesions and underscores the importance of integrating molecular findings with morphological and immunohistochemical data for the accurate classification and understanding of these neoplasms.

Molecular and Clinical Features of Pancreatic Acinar Cell Carcinoma: A Single-Institution Case Series

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods: We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023–2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, one had borderline resectable disease, and one had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (one patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes (BRCA1/2, PALB2, and ATM) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC.

Descriptive Analysis of Common Fusion Mutations in Papillary Thyroid Carcinoma in Hungary

Thyroid cancer is the most common type of endocrine malignancy. Papillary thyroid carcinoma (PTC) is its predominant subtype, which is responsible for the vast majority of cases. It is true that PTC is a malignant tumor with a very good prognosis due to effective primary therapeutic approaches such as thyroidectomy and radioiodine (RAI) therapy. However, we are often required to indicate second-line treatments to eradicate the tumor properly. In these scenarios, molecular therapies are promising alternatives, especially if specifically targetable mutations are present. Many of these targetable gene alterations originate from gene fusions, which can be found using molecular diagnostics like next-generation sequencing (NGS). Nonetheless, molecular profiling is far from being a routine procedure in the initial phase of PTC diagnostics. As a result, the mutation status, except for BRAF V600E mutation, is not included in risk classification algorithms either. This study aims to provide a comprehensive analysis of fusion mutations in PTC and their associations with clinicopathological variables in order to underscore certain clinical settings when molecular diagnostics should be considered earlier, and to demonstrate yet unknown molecular–clinicopathological connections. We conducted a retrospective fusion mutation screening in formalin-fixed paraffin-embedded (FFPE) PTC tissue samples of 100 patients. After quality evaluation by an expert pathologist, RNA isolation was performed, and then NGS was applied to detect 23 relevant gene fusions in the tumor samples. Clinicopathological data were collected from medical and histological records. To obtain the most associations from the multivariate dataset, we used the d-correlation method for our principal component analysis (PCA). Further statistical analyses, including Chi-square tests and logistic regressions, were performed to identify additional significant correlations within certain subsets of the data. Fusion mutations were identified in 27% of the PTC samples, involving nine distinct genes: RET, NTRK3, CCDC6, ETV6, MET, ALK, NCOA4, EML4, and SQSTM1. RET and CCDC6 fusions were associated with type of thyroidectomy, RAI therapy, smaller tumor size, and history of Hashimoto’s disease. NCOA4 fusion correlated with sex, multifocality, microcarcinoma character, history of goiter, and obstructive pulmonary disease. EML4 fusion was also linked with surgical procedure type and smaller tumor size, as well as the history of hypothyroidism. SQSTM1 fusion was associated with multifocality and a medical history of thyroid/parathyroid adenoma. NTRK3 and ETV6 fusions showed significant associations with Hashimoto’s disease, and ETV6, also with endometriosis. Moreover, fusion mutations were linked to younger age at the time of diagnosis, particularly the fusion of ETV6. The frequent occurrence of fusion mutations and their associations with certain clinicopathological metrics highlight the importance of integrating molecular profiling into routine PTC management. Early detection of fusion mutations can inform surgical decisions and therapeutic strategies, potentially improving clinical outcomes.

Tissue-Agnostic Targeting of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals and Future Directions.

NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normal NTRK can be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective.

Molecular Testing in Gliomas: What is Necessary in Routine Clinical Practice?

A number of molecular characteristics are essential for accurate diagnosis and prognostication in glioma. The 2021 WHO classification of brain tumors and recent Food and Drug Administration (FDA) pathology agnostic drug approvals highlight the importance of molecular testing in the management of glioma. For diffuse gliomas, it is important to identify IDH mutations, given the favorable clinical behavior and potential for using FDA approved IDH inhibitors in the near future. MGMT promoter methylation testing is the most established molecular marker for response to temozolomide in IDH wild-type glioblastoma and in turn impacts overall survival. Moreover, identification of certain mutations and molecular markers, such as BRAF V600E, hypermutation or elevated tumor-mutational burden and NTRK fusions allow for the use of FDA approved agents that are tumor-agnostic. Finally, molecular testing opens options for clinical trials that are essential for diseases with limited treatment options like gliomas.

ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic invivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.

Rare Oncogenic Fusions in Pediatric Central Nervous System Tumors: A Case Series and Literature Review

Background and Objectives: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. By contrast to their adult counterpart, the mutational landscape of pediatric CNS tumors is characterized by oncogenic fusions rather than multiple mutated genes. CNS pediatric tumors associated with oncogenic fusions represent a complex landscape of tumors with wide radiological, morphological and clinical heterogeneity. In the fifth CNS WHO classification, there are few pediatric CNS tumors for which diagnosis is based on a single oncogenic fusion. This work aims to provide an overview of the impact of rare oncogenic fusions (NTRK, ROS, ALK, MET, FGFR, RAF, MN1, BCOR and CIC genes) on pathogenesis, histological phenotype, diagnostics and theranostics in pediatric CNS tumors. We report four cases of pediatric CNS tumors associated with NTRK (n = 2), ROS (n = 1) and FGFR3 (n = 1) oncogenic fusion genes as a proof of concept. Cases presentation and literature review: The literature review and the cohort that we described here underline that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. Conclusions: These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification.

Epithelioid Fibrous Histiocytoma Is on a Continuum With Superficial ALK-rearranged Myxoid Spindle Cell Neoplasm: A Clinicopathologic Series of 35 Cases Including Alternate RET and NTRK3 Fusions.

Anaplastic lymphoma kinase (ALK) rearrangements drive most examples of epithelioid fibrous histiocytoma (EFH) and have been reported in an emerging family of receptor tyrosine kinase (RTK) fusion-positive mesenchymal neoplasms, including superficial ones described under the rubric of "superficial ALK-rearranged myxoid spindle cell neoplasm" (SAMS). Here, we describe 35 superficial tumors with SAMS morphology, which occurred in 18 females (51%) and 17 males at a median age at presentation of 39 years (range: 6 to 82y). Most tumors occurred on the lower extremity (25 tumors; 71%), followed by upper extremity (5; 14%), trunk (3; 9%), and face (2; 6%). Nine tumors were reported to have grown slowly before presentation, including >10 years in 2 cases. Tumors occurred primarily in the dermis (32 tumors; 91%) or subcutis (3; 9%); 8 dermal tumors extended into the subcutis. Median tumor size was 1.3cm (range: 0.5 to 8.0cm). Clinical follow-up was available for 12 patients (34%; range: 2mo to 21y; median: 2.7y), none of whom experienced metastasis. One incompletely resected tumor recurred locally at 19 months, and no other patients experienced recurrence. Histologically, tumors were characterized by bland spindle-to-ovoid cells showing whorled growth and myxoid-to-collagenous stroma. Recurrent features included an epidermal collarette (19/30; 63%), perivascular hyalinization (20/35; 57%), amianthoid collagen (14/35; 40%), and metaplastic ossification (2/35; 6%). Immunohistochemistry (IHC) demonstrated expression of ALK (24/31; 77%), CD34 (15/21; 71%), EMA (17/28; 61%), and S-100 (9/32; 28%). Eleven tumors showed hybrid morphologic features between EFH and SAMS; 9 of them (82%) showed cytomorphology typical of EFH but with whorled growth, myxoid stroma, and/or regions of spindle cell morphology. Two hybrid tumors showed sharp transitions between a region characteristic of EFH and a region characteristic of SAMS, with a concomitant sharp transition in EMA, CD34, and S-100 expression by IHC. Sequencing revealed ALK fusions in 15 of 19 tumors: 2 each with fusion partners FLNA, SQSTM1, and VCL, and 1 each with COL1A2, DCTN1, EML4, FXR1, MPRIP, PLEKHH2, PRKAR1A, SPECC1L, and TLN2. Thirteen of 14 ALK-rearranged tumors expressed ALK by IHC. Three tumors negative for ALK fusions instead harbored alternate RTK fusions (NCOA4::RET, TRIM27::RET, and VIM::NTRK3), and 1 tumor was negative for RTK alterations. CDKN2A/B deletions were found in 2 tumors with ALK fusions and both tumors with RET fusions. SAMS is on a morphologic and molecular genetic spectrum with EFH, with a similar body site distribution, frequent clinical presentation as an exophytic skin tumor, and invariably benign outcomes; we conclude that SAMS should be considered a histologic variant of EFH. Some morphologically typical examples harbor alternate RET and NTRK3 fusions, such that SAMS is not an appropriate designation for this morphologic class; instead, to highlight the clinicopathologic similarities to EFH, we propose the diagnostic term "myxoid spindle cell variant of epithelioid fibrous histiocytoma."

Novel therapies for pediatric low grade glioma.

Current biological findings provide new insights into the genetics driving growth of low-grade gliomas in pediatric patients. This has provided new targets for novel therapies. The purpose of this paper is to review novel therapies for pediatric low-grade gliomas that have been published in the past 24 months. Low-grade gliomas are often driven by mitogen activated protein kinase (MAPK) alterations either with BRAF V600E point mutations or BRAF fusions. Current advances have also highlighted novel fusions of fibroblast growth factor receptor (FGFR), myeloblastosis family of transcription factors (MYB), meningioma 1 tumor suppressor (MN1), neurotrophic receptor kinase family of receptors (NTRK), Kristen RAS (Rat Sarcoma Virus) oncogene homolog in mammals (KRAS), Receptor tyrosine kinase ROS proto oncogene 1 (ROS1), protein kinase C alpha (PRKCA), and platelet derive growth factor receptor (PDGFR) amplification. Novel therapies have been employed and are showing encouraging results in pediatric low-grade gliomas. Current trials are underway with newer generation pan RAF inhibitors and mitogen activated protein kinase - kinase (MEK) inhibitors. Other early phase clinical trials have provided safety data in pediatric patients targeting FGFR fusion, NTRK fusion, PDGFR amplification and ROS1 mutations. Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.

Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue

AbstractJuvenile xanthogranuloma (JXG) is a histiocytic neoplasm that usually presents in the skin. Rarely, extracutaneous localizations occur; the genetic drivers of this clinical variant of JXG remain incompletely characterized. We present detailed clinicopathologic and molecular data of 16 children with extracutaneous JXG and 5 adults with xanthogranulomas confined to the central nervous system (CNS) or soft tissue. Tissue samples were obtained through the Dutch Nationwide Pathology Databank and analyzed with an innovative sequencing technique capable of detecting both small genomic variants and gene rearrangements. Targetable kinase alterations were detected in 16 of 16 children and 1 of 5 adults. Alterations included CLTC::SYK fusions in 6 children and CSF1R mutations in 7 others; all aged <2 years with soft tissue tumors. One child had a CSF1R mutation and MRC1::PDGFRB fusion. Most were treated surgically, although spontaneous regression occurred in 1 of 6 with CLTC::SYK and 2 of 7 with CSF1R mutations, underscoring that treatment is not always necessary. Tumors with CLTC::SYK fusions generally lacked Touton giant cells but exhibited many other histologic features of JXG and concordant methylation profiles. Using multispectral immunofluorescence, phosphorylated–spleen tyrosine kinase expression was localized to CD163+ histiocytes; tumors with CLTC::SYK fusions also demonstrated mTOR activation, cyclin D1 expression, and variable phosphorylated–extracellular signal-regulated kinase expression. BRAFV600E was detected in 1 child and 1 adult with CNS xanthogranulomas; both responded to BRAF inhibition. Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion was detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.

Actionable alterations in glioblastoma: Insights from the implementation of genomic profiling as the standard of care from 2016 to 2023

Abstract Background In 2016, genomic profiling was implemented for patients with grade 4 primary brain tumors at Rigshospitalet, Denmark. The aim of this study was to discover actionable alterations and to match these with targeted therapies. Methods Between January 2016 and December 2023, 483 brain tumor patients were profiled. We retrieved clinical data and molecular data. Whole exome, whole genome, or panel sequencing, along with SNP array analyses, and RNA-seq were performed on resected primary tumor tissue. Alterations were classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) following the European Association of Neuro-Oncology (EANO) guideline on rational molecular testing. Results A total of 200 (41.4%) patients’ tumors harbored an alteration of interest according to the EANO guideline. Twenty (4.1%) patients had an ESCAT high-tier alteration (tier I or II), while 155 patients (32.1%) had an alteration corresponding to ESCAT IIIA. Thirty-five patients (7.2%) had an actionable alteration, and 15 (3.1%) received targeted therapy. The treated targets were BRAFV600E mutations, FGFR alterations, NTRK fusions, PDGFRA fusions, PTPRZ1-MET fusions, and TMB-high. The overall response rate was 20%, with a median duration of response of 12 months, and 47% achieved stable disease as the best response. Conclusions Genomic profiling uncovers alterations of interest in a substantial number of patients, but only a minority are considered by the Danish National Molecular Tumor Board to have actionable alterations, and even fewer receive targeted therapy. Nevertheless, factors, such as promising targets and the increasing availability of trials, may contribute to a future increase in the number of patients benefiting from targeted therapies based on genomic profiling.

Current Landscape of NTRK Inhibition for Pediatric CNS Tumors.

Over the last decade, as molecular platforms have permitted the characterization of the genomic landscape of pediatric central nervous system (CNS) tumors, pediatric neuro-oncology has dramatically transformed. NTRK fusions are oncogenic driver alterations that have been found in a multitude of tumor types, including pediatric CNS tumors. In recent years, NTRK inhibitors have emerged as a promising class of targeted therapies for pediatric CNS tumors with NTRK gene fusions. The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. These agents are well tolerated, although close to 20% of patients have spontaneous bone fractures. Given the existing data for patients with relapsed disease, clinical trials using NTRK inhibitors in the upfront setting is the next natural progression of efficacy testing and many are currently underway. There are still several challenges that need to be addressed to optimize the use of NTRK inhibitors and identify the patients with NTRK fusion-positive CNS tumors who are most likely to benefit from them. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.

NTRK Fusion as an Acquired Mechanism of Resistance to Selpercatinib in RET Positive Thyroid Cancer

Background: Rearrangement during Transfection (RET) proto-oncogene is involved in the pathogenesis of various thyroid cancer subtypes and drugs that block the RET tyrosine kinase pathways are used in the management of locally advanced and metastatic Medullary Thyroid Cancer (MTC). Acquired resistance to RET inhibitors likely occurs via two different mechanisms: (1) On-target mutations that prevent drug binding and (2) Activated alternative mechanisms which bypass the targeted kinase. We present a unique mechanism of selpercatinib resistance via secondary NTRK fusion mutation in a case of RET altered medullary thyroid cancer. Case Presentation: The patient is a 72-year-old female with stage III metastatic MTC who developed recurrence with newly found RET mutation 7 years after complete surgical resection. Despite initial stable response with selpercatinib for 2 years she rapidly progressed with widespread disease. Cell-free DNA (cfDNA) testing done at the time of progression revealed an NTRK1 fusion. Unfortunately, the patient succumbed to the disease despite starting targeted therapy with larotrectinib. Conclusion: This case highlights the importance of further investigation into mechanisms of resistance to RET inhibitors and drug studies directed towards overcoming them

Pediatric Fibromatosis Lacks the Internal Tandem Duplication of EGFR Seen in Congenital Mesoblastic Nephroma.

Classical and mixed congenital mesoblastic nephroma (CMN) are characterized by an internal tandem duplication (ITD) of the EGFR gene, in contrast to cellular CMN that usually harbors an ETV6::NTRK3 gene fusion. This same fusion occurs in infantile fibrosarcoma, and this tumor can be considered as the soft tissue equivalent of cellular CMN. A soft tissue equivalent of classic/mixed CMN remains undefined at the genetic level. Since classical CMN resembles fibromatosis of soft tissue histologically, we asked whether fibromatosis in children might show EGFR ITD. ITD was investigated using the polymerase chain reaction and primers for exons 18 and 25 of the EGFR gene. Seven of the eight cases of classical or mixed CMN were positive by this approach, but none of the five cellular CMNs. Of 11 cases of fibromatosis (six plantar, two digital, and three desmoid), none were positive for EGFR ITD. Within the limits of this small study, we conclude that pediatric fibromatosis is likely not characterized by EGFR ITD. There are isolated reports of pediatric soft tissue tumors that harbor EGFR ITD, but these have the appearance of infantile fibrosarcoma or mixed CMN rather than fibromatosis. We did not find any such cases, since all 14 cases of infantile fibrosarcoma in our study had an ETV6::NTRK3 fusion. The soft tissue tumors with EGFR ITD are not a morphologic match for the low-grade histology of classical CMN. Whether they have a similar favorable biology or behave more like fibrosarcoma with an ETV6::NTRK3 fusion or an alternative fusion involving other kinases remains to be determined.

NTRK fusion cervical sarcoma with rhabdoid cells and misleading molecular testing.

NTRK fusion cervical sarcoma with rhabdoid cells and misleading molecular testing.

NTRK gene alterations were enriched in hepatoid or enteroblastic differentiation type of gastric cancer

AimsCurrently, the clinicopathological characteristics of gastric cancer (GC) with oncogenic NTRK alterations are not well known. Although NTRK fusion has been identified as prevalent in DNA mismatch repair protein deficient...

Pyrazolo[1,5-a]pyrimidine as a Prominent Framework for Tropomyosin Receptor Kinase (Trk) Inhibitors-Synthetic Strategies and SAR Insights.

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.