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Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors
Author(s) -
Chen Hui,
Isozaki Koji,
Kinoshita Kazuo,
Ohashi Akiko,
Shinomura Yasuhisa,
Matsuzawa Yuji,
Kitamura Yukihiko,
Hirota Seiichi
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11025
Subject(s) - imatinib , cancer research , stromal cell , protein kinase b , biology , proto oncogene proteins c kit , in vivo , microbiology and biotechnology , cell growth , transfection , cell culture , signal transduction , stem cell factor , haematopoiesis , stem cell , biochemistry , genetics , myeloid leukemia
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 del559–560 , KIT 642Glu , and KIT 820Tyr ) 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. In vitro studies on cell proliferation using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenylcetrazolium bromide colorimetric assay and in vivo 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 820Tyr . Imatinib potently inhibited the proliferation of cells transfected with KIT 820Tyr 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 in vitro and in vivo although the effect of Imatinib on KIT 820Tyr was weaker than that on KIT del559–560 or KIT 642Glu . © 2003 Wiley‐Liss, Inc.