A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors

TLDR

KIT gain‑of‑function mutations drive gastrointestinal stromal tumor development, and imatinib, a selective tyrosine‑kinase inhibitor of KIT, ABL, and PDGFR, represents a new paradigm of targeted therapy for GISTs. We followed 12 GIST patients who initially achieved near‑complete response to imatinib, noting that 7 carried exon 11 mutations and 5 exon 9 mutations, and that within 31 months six rapidly progressive, imatinib‑resistant peritoneal implants emerged in five patients while quiescent residual tumors persisted in seven. All six resistant implants harbored a novel KIT missense mutation, 1982T→C (Val654Ala) in tyrosine‑kinase domain 1, which was absent from pre‑ and post‑imatinib residual quiescent tumors and was strongly correlated with resistance, occurring on the allele bearing the original activating mutation.

Abstract

Abstract KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T→C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.