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

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Simona Gloazzo,
  • Marta Sbaraglia,
  • Elena Bellan,
  • Daniela Gasparotto,
  • Elena Belli,
  • Davide Baldazzi,
  • Gabriella Rossi,
  • Elena Magnani,
  • Maria Pia Rosito,
  • Andrea Carnevali,
  • Sara Piccinin,
  • Angelo Paolo Dei Tos,
  • Roberta Maestro

摘要

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.