KIT Mutation-NTRK fusion oncogenic driver switch: a novel mechanism of acquired imatinib resistance in GIST

TL;DR

This paper reports a new mechanism of imatinib resistance in GIST where a KIT mutation switches to an NTRK3 fusion, suggesting NTRK inhibitors as a potential treatment.

Contribution

The study identifies the first case of an NTRK fusion as a secondary event causing imatinib resistance in GIST.

Findings

The relapsed tumor lost KIT expression and showed a dedifferentiated phenotype with an EML4::NTRK3 fusion.

EML4::NTRK3 confers imatinib resistance but makes GIST cells sensitive to NTRK inhibitors.

This case highlights the need to test for NTRK alterations in resistant tumors to explore new therapies.

Abstract

Imatinib is the first-line treatment for advanced gastrointestinal stromal tumors (GISTs) harboring KIT or PDGFRA mutations. Unfortunately, resistance invariably develops, typically through secondary KIT/PDGFRA mutations. Here, we describe an unprecedented case of acquired imatinib resistance associated with an oncogenic driver switch, from a KIT mutation to an NTRK3 fusion. The index case was a KIT exon 11-mutated gastric GIST that progressed on imatinib. Despite retaining the original KIT mutation and DOG1 expression, the relapsed tumor lost KIT expression and exhibited a dedifferentiated phenotype. Transcriptomic profiling revealed a de novo EML4::NTRK3 gene fusion. In vitro modeling demonstrated that EML4::NTRK3 confers imatinib resistance, while sensitizing GIST cells to NTRK inhibitors. This first reported instance of an NTRK fusion as a secondary event in GIST progression underscores the importance of testing for NTRK alterations in tumors that have developed resistance to tyrosine kinase inhibitors to ensure patients are offered all available therapeutic options.

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