Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors
, Journal Article
Chen, H; Isozaki, K; Kinoshita, K; Ohashi, A; Shinomura, Y; Matsuzawa, Y; Kitamura, Y; Hirota, S
Published in: International Journal of Cancer
Mutations of proto‐oncogene c‐KIT in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. To investigate the effect of Imatinib on various c‐KIT mutations found in GISTs, we examined kinase activity of KIT, cell proliferation and tumorigenicity of transfectants with various c‐KIT mutations. Murine lymphoid Ba/F3 cells transfected with one of the three types of mutants (KIT, KIT, and KIT) or wild‐type KIT were used for the experiments. Phosphorylation of KIT, mitogen‐activated protein (MAP) and Akt was studied by immunoblotting with or without immunoprecipitation. studies on cell proliferation using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenylcetrazolium bromide colorimetric assay and tumorigenicity assay using nude mice were also carried out. Imatinib could inhibit the KIT, MAP and Akt phosphorylation of all the transfectants but had a weaker effect on KIT. Imatinib potently inhibited the proliferation of cells transfected with KIT at the concentration of 10 μM whereas it inhibited the other 3 types at 1 μM. Moreover, Imatinib could inhibit the tumor formation in nude mice transplanted with transfectants. In various types of activating mutant KIT, Imatinib could inhibit the constitutive activation of KIT signal transduction and cell proliferation both and although the effect of Imatinib on KIT was weaker than that on KIT or KIT. © 2003 Wiley‐Liss, Inc.
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