title: Constitutive activation of c-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296.
abstract: The c-kit receptor tyrosine kinase (KIT) is constitutively activated by 2 types of naturally occurring mutations, the Val559-->Gly (G559) mutation in the juxtamembrane domain and the Asp814-->Val (V814) mutation in the catalytic domain. We evaluated the effects of the tyrosine kinase inhibitors STI571 and AG1296 on BaF3 cells expressing wild-type KIT (KIT(WT)) or activating mutants of KIT (KIT(G559) and KIT(V814)) in the presence or absence of the KIT ligand, stem cell factor (SCF). Both STI571 and AG1296 inhibited SCF-dependent activation of KIT(WT) and SCF-independent activation of KIT(G559) more efficiently, whereas SCF-independent activation of KIT(V814) was scarcely affected. Furthermore, both inhibitors inhibited SCF-dependent growth of BaF3-KIT(WT) cells and, with higher potencies, SCF-independent growth of BaF3-KIT(G559) cells through the induction of apoptosis. In contrast, the inhibitors had little or no effect on SCF-independent growth of BaF3-KIT(V814) cells or on IL-3-dependent growth of BaF3-Mock cells. These results suggested that both inhibitors may be effective therapeutic agents for oncogenic KIT with the juxtamembrane domain mutation, but not with the catalytic domain mutation, and that the activation mechanism of the catalytic domain mutant KIT is complex and entirely different from that of the wild-type KIT or the juxtamembrane domain mutant KIT.
authors.affiliation: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ueda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ikeda
authors.forename: Masao
authors.initials: M
authors.lastname: Mizuki
authors.forename: Jun
authors.initials: J
authors.lastname: Ishiko
authors.forename: Itaru
authors.initials: I
authors.lastname: Matsumura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Shibayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugahara
authors.forename: Emi
authors.initials: E
authors.lastname: Takai
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Takashi
authors.initials: T
authors.lastname: Machii
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068877:Imatinib Mesylate; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit