title: 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-alpha.
abstract: 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, Val561 to Asp and Asp842 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 microM in cells expressing mutant PDGFRA with Val561 to Asp. However, in cells expressing mutant PDGFRA with Asp842 to Val, imatinib almost completely inhibited autophosphorylation of mutant PDGFRA and phosphorylation of MAPK and Akt at 1.0 microM. The concentration contributing to complete inhibition of in vitro cell proliferation was 10 microM. 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.
authors.affiliation: Department of Pathology, Osaka University Medical School, Suita, Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohashi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Koji
authors.initials: K
authors.lastname: Isozaki
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D023421:Models, Animal; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D017154:Stromal Cells / Q000473:pathology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011994:Recombinant Proteins; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases