title: MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth.
abstract: Imatinib mesylate (imatinib) inhibits the c-Kit-dependent tyrosine kinase activities and highly effective in the treatment of CML and GIST patients. Although pancreatic cancer is reported to express c-Kit, imatinib does not effectively inhibit pancreatic cancer cell growth at physiological concentrations. Therefore, we investigated the mechanism of resistance of pancreatic cancer to imatinib treatment. Imatinib inhibited growth of pancreatic cancer cell lines in concentration and time-dependent fashion regardless of c-Kit expression. However, 5 microM imatinib, which is almost a mean maximal plasma concentration in clinical setting, failed to suppress pancreatic cancer cell growth. Western blot analysis demonstrated that 5 microM imatinib treatment for 1h activated the MEK-MAPK pathway and the activation was independent of Ras activation. Administration of 5 microM imatinib and 1 microM U0126 (MEK inhibitor) significantly suppressed pancreatic cell growth. Our results indicate that a combination therapy of imatinib and MEK inhibitor can be a new therapeutic strategy to suppress the progression of pancreatic cancer.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takayama
authors.forename: Toshio
authors.initials: T
authors.lastname: Kokuryo
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Masato
authors.initials: M
authors.lastname: Nagino
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Senga
authors.forename: Michinari
authors.initials: M
authors.lastname: Hamaguchi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D010879:Piperazines; D011743:Pyrimidines; C113580:U 0126; D000068877:Imatinib Mesylate; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases