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 Kit mutations on GIST development and imatinib sensitivity, we engineered a mouse model carrying in the endogenous Kit locus both the Kit(V558Δ) mutation found in a familial case of GIST and the Kit(T669I) (human KIT(T670I)) "gatekeeper" mutation found in imatinib-resistant GIST patients. Similar to Kit(V558/+) mice, Kit(V558;T669I/+) mice developed gastric and colonic interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast to the single-mutant Kit(V558/+) control mice, treatment of the Kit(V558;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;T669I/+) mice with sunitinib or sorafenib. Although tumor lesions were smaller in Kit(V558;T669I/+) mice than in single-mutant mice, both interstitial cell of Cajal hyperplasia and mast cell hyperplasia were exacerbated in Kit(V558;T669I/+) mice. Strikingly, the Kit(V558;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.
Developmental Biology, Sloan-Kettering Institute, New York, NY 10065, USA.
Benedikt
B
Bosbach
Shayu
S
Deshpande
Ferdinand
F
Rossi
Jae-Hung
JH
Shieh
Gunhild
G
Sommer
Elisa
E
de Stanchina
Darren R
DR
Veach
Joseph M
JM
Scandura
Katia
K
Manova-Todorova
Malcolm A S
MA
Moore
Cristina R
CR
Antonescu
Peter
P
Besmer
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D019070:Cell Lineage; D000069439:Dasatinib; D004195:Disease Models, Animal; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004912:Erythrocytes / Q000166:cytology*; D005091:Exons; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics*; D000068877:Imatinib Mesylate; D051379:Mice; D009154:Mutation; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D011086:Polycythemia / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib