Re-profiling of protein kinase inhibitors for next generation molecular target therapy

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590469
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hokkaido University
• Principal Investigator: TSUDA Masumi 北海道大学, 医学(系)研究科(研究院), 講師 (30431307)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 腫瘍 / 分子標的治療 / キナーゼ阻害剤 / 薬剤耐性 / シグナル伝達

Outline of Final Research Achievements

Several molecular therapeutics targeting protein tyrosine kinases have recently been attempted; however, an emerging drug resistance is a crucial issue. Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. Despite technological advances in surgery, combined with regimens of radiotherapy and new generation chemotherapy with temozolomide, the median survival is still 15 months. Here, we established cell lines acquired drug resistance to individual tyrosine kinase inhibitor (TKI) for EGFR, c-Met, and PDGFR that highly expressed in GBM, and characterized the underlying mechanisms. We found that c-Met inhibitor effectively abrogated TKIs-dependent enhancement of phosphorylation of EGFR, although it did not effect on the ATP-binding ability of EGFR. In addition, the combination therapy of c-Met and PI3K inhibitors might be a powerful approach to abolish the TKI resistance for molecular target therapy in GBM, by inhibiting phosphorylations of Akt, Src, and p38 MAPK.

Free Research Field

腫瘍のシグナル伝達研究