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

Developmental Biology, Sloan-Kettering Institute, New York, NY 10065, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2012; 109(34):E2276-E2283. DOI: 10.1073/pnas.1115240109
Source: PubMed


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 Kit mutations on GIST development and imatinib sensitivity, we engineered a
mouse model carrying in the endogenous Kit locus both the KitV558Δ mutation found in a familial case of GIST and the KitT669I (human KITT670I) “gatekeeper” mutation found in imatinib-resistant GIST patients. Similar to KitV558∆/+ mice, KitV558∆;T669I/+ mice developed gastric and colonic interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast to the single-mutant
KitV558∆/+ control mice, treatment of the KitV558∆;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 KitV558∆;T669I/+ mice with sunitinib or sorafenib. Although tumor lesions were smaller in KitV558∆;T669I/+ mice than in single-mutant mice, both interstitial cell of Cajal hyperplasia and mast cell hyperplasia were exacerbated in
KitV558∆;T669I/+ mice. Strikingly, the KitV558∆;T669I/+ mice developed a pronounced polycythemia vera-like erythrocytosis in conjunction with microcytosis. This mouse model should
be useful for preclinical 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.

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