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

: 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.