Imatinib resistance and microcytic erythrocytosis in a KitV558Δ; T669I/+ gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Most gastrointestinal stromal tumors (GISTs) harbor a gain-of-function mutation in the Kit receptor. GIST patients treated with the tyrosine kinase inhibitor imatinib frequently develop imatinib resistance as a result of second-site Kit mutations. To investigate the consequences of second-site Kitmutations on GIST development and imatinib sensitivity, we engineered a mouse model carrying in the endogenous Kit locus both the Kit(V558 Delta) mutation found in a familial case of GIST and the Kit(T669I) (human KITT670I) "gatekeeper" mutation found in imatinib-resistant GIST patients. Similar to Kit(V558 Delta/+) mice, Kit(V558 Delta;T669I/+) mice developed gastric and colonic interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast to the single-mutant Kit(V558 Delta/+) control mice, treatment of the Kit(V558 Delta;T669I/+) mice with either imatinib or dasatinib failed to inhibit oncogenic Kit signaling and GIST growth. However, this resistance could be overcome by treatment of Kit(V558 Delta;T669I/+) mice with sunitinib or sorafenib. Although tumor lesions were smaller in Kit(V558 Delta;T669I/+) mice than in single-mutant mice, both interstitial cell of Cajal hyperplasia and mast cell hyperplasia were exacerbated in Kit(V558 Delta;T669I/+) mice. Strikingly, the Kit(V558 Delta;T669I/+) mice developed a pronounced polycythemia vera-like erythrocytosis in conjunction with microcytosis. This mouse model should be useful for pre-clinical studies of drug candidates designed to overcome imatinib resistance in GIST and to investigate the consequences of oncogenic KIT signaling in hematopoietic as well as other cell lineages.