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Different inhibitory effect of imatinib on phosphorylation of mitogen‐activated protein kinase and Akt and on proliferation in cells expressing different types of mutant platelet‐derived growth factor receptor‐α
Author(s) -
Ohashi Akiko,
Kinoshita Kazuo,
Isozaki Koji,
Nishida Toshirou,
Shinomura Yasuhisa,
Kitamura Yukihiko,
Hirota Seiichi
Publication year - 2004
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.20305
Subject(s) - pdgfra , autophosphorylation , protein kinase b , mapk/erk pathway , imatinib , platelet derived growth factor receptor , cancer research , wortmannin , cell growth , phosphorylation , microbiology and biotechnology , pi3k/akt/mtor pathway , mutant , biology , imatinib mesylate , stromal cell , protein kinase a , growth factor , signal transduction , biochemistry , gist , receptor , gene , myeloid leukemia
Most gastrointestinal stromal tumors (GISTs) have gain‐of‐function mutations of the c‐ kit gene. Previously, we found 2 types of gain‐of‐function mutation of the PDGFRA gene, Val 561 to Asp and Asp 842 to Val, in about half of GISTs without c‐ kit gene mutations. Although the inhibitory effect of imatinib on various types of activating mutant KIT has been well examined, that on the activating mutant PDGFRA has not been fully investigated. In the present study, we examined the effect of imatinib on autophosphorylation of mutant PDGFRA, phosphorylation of MAPK and of Akt and in vitro cell proliferation using murine Ba/F3 cells stably transfected with one of the 2 murine‐type mutated PDGFRA cDNAs. Imatinib almost completely inhibited autophosphorylation of mutant PDGFRA, phosphorylation of MAPK and Akt as well as in vitro cell proliferation at the concentration of 0.01 μM in cells expressing mutant PDGFRA with Val 561 to Asp. However, in cells expressing mutant PDGFRA with Asp 842 to Val, imatinib almost completely inhibited autophosphorylation of mutant PDGFRA and phosphorylation of MAPK and Akt at 1.0 μM. The concentration contributing to complete inhibition of in vitro cell proliferation was 10 μM. Ba/F3 cells expressing mutant PDGFRA are a good model to investigate the mechanism of cell proliferation or growth inhibition by imatinib in mutant PDGFRA‐driven cells. © 2004 Wiley‐Liss, Inc.