MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth

Imatinib mesylate (imatinib) inhibits the c-Kit-dependent tyrosine kinase activities and highly effective ill 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 mu M 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 mu M imatinib treatment for 1 h activated the MEK-MAPK pathway and the activation was independent of Ras activation. Administration of 5 mu M imatinib and 1 mu M U0126 (MEK inhibitor) significantly suppressed pancreatic cell growth. Our results indicate that a combination therapy of imatinib and MEK inhibitor call be a new therapeutic strategy to suppress the progression of pancreatic cancer. (C) 2008 Elsevier Ireland Ltd. All rights reserved.