Activity of AT13387, a novel, non-ansamycin inhibitor of heat shock protein 90, against gastrointestinal stromal tumors (GIST).

105 Background: AT13387 is a second-generation potent, novel non-ansamycin HSP90 inhibitor (Kd 0.71nM). The majority of GIST tumors are characterized by activating mutations of c-KIT, an HSP90 client protein. Secondary resistance mutations within c-KIT limit clinical responses to TKIs. The dependence of c-KIT and its mutated forms on HSP90 suggests that HSP90 inhibition may be a valuable treatment option for imatinib-sensitive and resistant clones. In vitro, AT13387 inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and imatinib-resistant (GIST430, GIST48) cell lines. In vivo, AT13387 demonstrated anti-tumor activity in the imatinib-sensitive (GIST-PSW) and imatinib-resistant (GIST430) xenograft models. Induction of HSP70, depletion of phospho-c-KIT and inhibition of c-KIT signaling were observed in both models. Combination treatment of imatinib and AT13387 in the GIST430 model was well tolerated and significantly enhanced tumor growth inhibition over either monotherapies. Methods: In a ...