Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors.Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action.Here we show that Gleevec can act on host DCs to promote NK cell activation.DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT.Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner.Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN- production by NK cells, correlating with an enhanced antitumor response.These data point to a novel mode of antitumor action for Gleevec.Nonstandard abbreviations used: bi-injection daily (bid); bone marrow-derived DC (BM-DC); break point cluster region/Abelson leukemia virus (BCR/ABL); chronic myelogenous leukemia (CML); c-kit loss-of-function mutation (W/Wv); fms-like tyrosine 3 kinase ligand (FL); gastrointestinal stromal tumor (GIST); progression-free survival (PFS); stem cell factor (SCF); transporter associated with antigen processing (TAP).