In vitro activity of sorafenib against imatinib- and sunitinib-resistant kinase mutations associated with drug-resistant GI stromal tumors

10500 Background: Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are targets of imatinib (front-line therapy) or sunitinib (second-line therapy). Resistance to imatinib (IM) or sunitinib (SU) is commonly associated with the acquisition of secondary kinase mutations. In phase II studies, sorafenib (SOR), which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in GIST patients after failure of IM and SU. We evaluated the in vitro activity of SOR against IM and/or SU resistant kinases. Methods: Kinase mutants were biochemically profiled for SOR, SU, and IM sensitivity by measuring inhibition of kinase phosphorylation after drug treatment in mutant-expressing CHO cells. We also tested the biochemical and cellular activity of SOR and IM against GIST cells derived from IM-resistant tumor clones. Results: SOR had superior potency to IM against IM-resistant KIT secondary mutations involving the ATP bin...