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Complete response to larotrectinib treatment in a patient with papillary thyroid cancer harboring an ETV6-NTRK3 gene fusion.

ABSTRACT: Larotrectinib, a highly selective TRK inhibitor, was administered to a patient with rapidly progressing radioactive iodine-refractory papillary NTRK3 fusion-positive thyroid cancer. The patient achieved a durable (sustained for 11 months) complete response after 2 months of treatment and complete intracranial responses in metastatic brain lesions after 7 months of treatment. Larotrectinib may provide a therapeutic route for patients with RAI-R-differentiated thyroid cancer who might otherwise have few treatment options.

SUBMITTER: Pitoia F

PROVIDER: S-EPMC8077291 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Clinical response to larotrectinib in adult Philadelphia chromosome-like ALL with cryptic ETV6-NTRK3 rearrangement.

Project description:Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subtype of Ph-negative ALL that molecularly resembles Ph-positive ALL. It shares the adverse prognosis of Ph-positive ALL, but lacks the BCR-ABL1 fusion oncogene. Instead, Ph-like ALL is associated with alternative mutations in signaling pathways. We describe a case of Ph-like ALL that harbored 2 genomic alterations, which activated signaling, an NRASGly12Asp mutation, and an ETV6-NTRK3 rearrangement. Initially, the NRAS mutation was detected at high frequency, whereas the gene fusion was only detectable with a targeted next-generation sequencing-based fusion assay, but not by fluorescence in situ hybridization analysis. The disease failed to respond to multiagent chemotherapy but investigational CD19-directed chimeric antigen receptor T-cell therapy resulted in a complete remission. However, the leukemia relapsed after 6 weeks. Intriguingly, the NRAS mutation was extinguished during the chimeric antigen receptor T-cell therapy and did not contribute to the relapse, which was instead associated with a rise in ETV6-NTRK3. The relapsed leukemia progressed with further chemo- and immunotherapy but was controlled for 6 weeks with substantial leukemic cytoreduction using the TRK inhibitor larotrectinib. Unfortunately, recovery of normal hematopoiesis was only marginal and the patient eventually succumbed to infections. These results demonstrate that larotrectinib has clinical activity in ETV6-NTRK3-associated Ph-like ALL.

| S-EPMC6960464 | biostudies-literature

ETV6-NTRK3 fusion oncoprotein transduces NIH 3T3 cells

2007-12-14 | GSE9354 | GEO

Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia.

Project description:BACKGROUND: Characterization of novel fusion genes in acute leukemia is important for gaining information about leukemia genesis. We describe the characterization of a new ETV6 fusion gene in acute myeloid leukemia (AML) FAB M0 as a result of an uncommon translocation involving chromosomes 12 and 15. METHODS: The ETV6 locus at 12p13 was shown to be translocated and to constitute the 5' end of the fusion product by ETV6 break apart fluorescence in situ hybridisation (FISH). To identify a fusion partner 3' rapid amplification of cDNA-ends with polymerase chain reaction (RACE PCR) was performed followed by cloning and sequencing. RESULTS: The NTRK3 gene on chromosome 15 was found to constitute the 3' end of the fusion gene and the underlying ETV6-NTRK3 rearrangement was verified by reverse transcriptase PCR. No RNA of the reciprocal NTRK3-ETV6 fusion gene could be detected. CONCLUSION: We have characterized a novel ETV6-NTRK3 fusion transcript which has not been previously described in AML FAB M0 by FISH and RACE PCR. ETV6-NTRK3 rearrangements have been described in secretory breast carcinoma and congenital fibrosarcoma.

| S-EPMC3063188 | biostudies-literature

Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1.

Project description: Not available

| S-EPMC7055910 | biostudies-literature

Successful Targeted Therapy of Refractory Pediatric <i>ETV6-NTRK3</i> Fusion-Positive Secretory Breast Carcinoma.

Project description: Not available

| S-EPMC5880290 | biostudies-literature

Infantile Fibrosarcoma With NTRK3-ETV6 Fusion Successfully Treated With the Tropomyosin-Related Kinase Inhibitor LOXO-101.

Project description:Infantile fibrosarcoma (IFS) is a rare pediatric cancer typically presenting in the first 2 years of life. Surgical resection is usually curative and chemotherapy is active against gross residual disease. However, when recurrences occur, therapeutic options are limited. We report a case of refractory IFS with constitutive activation of the tropomyosin-related kinase (TRK) signaling pathway from an ETS variant gene 6-neurotrophin 3 receptor gene (ETV6-NTRK3) gene fusion. The patient enrolled in a pediatric Phase 1 trial of LOXO-101, an experimental, highly selective inhibitor of TRK. The patient experienced a rapid, radiographic response, demonstrating the potential for LOXO-101 to provide benefit for IFS harboring NTRK gene fusions.

| S-EPMC5074243 | biostudies-literature

ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex.

Project description:To better understand the cellular origin of breast cancer, we developed a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Wap-Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that, in nulliparous Wap-Cre;EN females, committed alveolar bipotent or CD61(+) luminal progenitors are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given the increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of preclinical models.

| S-EPMC2175032 | biostudies-literature

Mechanisms of targeted therapy resistance in a pediatric glioma driven by <i>ETV6-NTRK3</i> fusion.

Project description:Chromosomal rearrangements of the NTRK genes generate kinase fusions that are targetable oncogenic drivers in diverse adult and pediatric malignancies. Despite robust clinical response to targeted NTRK inhibition, the emergence of therapeutic resistance poses a formidable clinical challenge. Here we report the characterization of an ETV6-NTRK3 fusion-driven pediatric glioma that progressed through NTRK-targeted treatments with entrectinib and selitrectinib. Genetic analysis of multifocal recurrent/resistant lesions identified a previously uncharacterized NTRK3 p.G623A and a known p.G623E resistance mutation, in addition to other alterations of potential pathogenic impact. Functional studies employing heterologous reconstitution model systems and patient-derived tumor cell lines establish that NTRK3G623A and NTRK3G623E mutated kinases exhibit reduced sensitivity to entrectinib and selitrectinib, as well as other NTRK inhibitors tested herein. In summary, this genetic analysis of multifocal recurrent/resistant glioma driven by ETV6-NTRK3 fusion captured a cross-section of resistance-associated alterations that, based on in vitro analysis, likely contributed to resistance to targeted therapy and disease progression.

| S-EPMC8559620 | biostudies-literature

Transcription profiling of mouse model for ETV6-NTRK3 (EN) fusion oncoprotein expresson

Project description:We report a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed bipotent or CD61+ luminal alveolar progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. We showed that forced expression of a dominant negative version of c-Jun (TAM67) in EN-transduced Eph4 mammary epithelial cells impairs their ability to form tumors in immunodeficient nude mice, thus provided validation that EN-initiated mammary tumorigenesis is largely mediated through the AP1 complex. Experiment Overall Design: To validate that EN-initiated mammary tumorigenesis is largely mediated through the AP1 complex, we generated EN-transduced Eph4 (EN-Eph4) mammary epithelial cells as well as EN-Eph4 cells co-expressing a dominant negative version of c-Jun (TAM67), and transplanted them into nude mice. We then isolated total RNAs from resulted tumors and collected their expression profiles using Affymetrix mouse MOE 430.2 chips.

2008-06-16 | E-GEOD-9353 | biostudies-arrayexpress

Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma.

Project description:Morphological, cytogenetic, and biological evidence supports a relationship between congenital (infantile) fibrosarcoma (CFS) and congenital mesoblastic nephroma (CMN). These tumors have a very similar histological appearance, and they are both associated with polysomies for chromosomes 8, 11, 17, and 20. Recently, CFS was shown to contain a novel t(12; 15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. The aims of this study were to determine whether congenital mesoblastic nephroma contains the t(12;15)(p13;q25) translocation and ETV6-NTRK3 gene fusion and whether ETV6-NTRK3 fusions, in CMN and CFS, antedate acquisition of nonrandom chromosome polysomies. To address these aims, we evaluated 1) ETV6-NTRK3 fusion transcripts by reverse transcriptase polymerase chain reaction and sequence analysis, 2) genomic ETV6-region chromosomal rearrangement by fluorescence in situ hybridization, and 3) chromosomal polysomies by karyotyping and fluorescence in situ hybridization. We report ETV6-NTRK3 fusion transcripts and/or ETV6-region rearrangement in five of six CMNs and in five of five CFSs. The ETV6-NTRK3 fusion transcripts and/or ETV-region chromosome rearrangements were demonstrated in two CMNs and one CFS that lacked chromosome polysomies. These findings demonstrate that t(12;15) translocation, and the associated ETV6-NTRK3 fusion, can antedate acquisition of chromosome polysomies in CMN and CFS. CMN and CFS are pathogenetically related, and it is likely that they represent a single neoplastic entity, arising in either renal or soft tissue locations.

| S-EPMC1853403 | biostudies-literature

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