Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients.

Purpose: KIT is the major oncogenic driver of gastrointestinal stromal tumors( GIST). Imatinib, sunitinib, and regorafenibare approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutationsin KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinibin preclinical models and describe initial characterization of its activity in patients with GIST. Experimental Design: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenibagainst mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib–KIT costructure was also determined. The clinical activity of ponatinibwas examined in three patients with GISTpreviously treated with all three FDA-approved agents. Results: In engineered and GIST-derived cell lines, ponatinibpotently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinibalso induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinibwas sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib(30 mg daily) displayed encouraging clinical activity in two of three patients with GIST. Conclusion: Ponatinibpossesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinibin patients with GIST. Clin Cancer Res; 20(22); 5745–55. ©2014 AACR .