Abstract

Neurotrophic tyrosine receptor kinase (NTRK) fusions are promising molecular targets that have been described in a broad range of malignant tumours. Fusions commonly lead to the expression of chimeric proteins with constitutive tyrosine kinase activation that drives tumorigenesis. Despite a low prevalence among most solid tumours (<1%), the first encouraging results with pan‐NTRK tyrosine kinase inhibitors (TKIs) such as larotrectinib or entrectinib stimulated the search for eligible patients. Here, we report the first three cases of osteosarcoma harbouring NTRK fusions, among 113 patients sequenced. It is also the first report on NTRK fusions within a tumour type characterised by highly rearranged genomes and abundant passenger mutations. Whereas the presence of NTRK gene fusions in many tumours is considered to be one of the main driver events for tumour progression, the three chimeric transcripts described here appear non‐functional and likely represent randomly occurring passenger alterations. Particularly in tumours with complex karyotypes, it may therefore be advisable to specifically investigate the fusion transcripts for functional impact before considering targeted treatment approaches using pan‐NTRK TKIs.

Highlights

  • Expressed in neuronal tissue, the NTRK1, NTRK2 and NTRK3 genes promote proliferation and survival of neuronal cells through the activation of the MAP-kinase, PLC-γ and PI3K-AKT signalling pathways [1]

  • Gene fusions between the tyrosine kinase domain of Neurotrophic tyrosine receptor kinase (NTRK) genes and different upstream partners lead to ectopic expression of constitutively active chimeric proteins

  • These tumours can be divided into a group of rare malignancies displaying a high prevalence (>80%) and a group of various other cancer types, in which NTRK fusions are generally infrequent (

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Summary

Introduction

Expressed in neuronal tissue, the NTRK1, NTRK2 and NTRK3 genes promote proliferation and survival of neuronal cells through the activation of the MAP-kinase, PLC-γ and PI3K-AKT signalling pathways [1]. Gene fusions between the tyrosine kinase domain of NTRK genes and different upstream partners lead to ectopic expression of constitutively active chimeric proteins. The list of cancer types in which NTRK fusions have been identified has kept growing since their discovery in 1982 [2]. These tumours can be divided into a group of rare malignancies displaying a high prevalence (>80%) and a group of various other cancer types, in which NTRK fusions are generally infrequent (

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