Development of treatment strategy against KRAS mutant cancer by targeting PI3K and ERK

2015 Fiscal Year Final Research Report

• Project/Area Number: 26830105
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kanazawa University
• Principal Investigator: Hiromichi Ebi 金沢大学, がん進展制御研究所, 准教授 (00645145)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: がん / KRAS / MEK阻害剤 / フィードバック

Outline of Final Research Achievements

KRAS is frequently mutated in a variety of cancers including lung cancer. Whereas the mitogen-activated protein kinase (MAPK) is a well-known effector pathway of KRAS, blocking this pathway with clinically-available MAPK inhibitors is relatively ineffective. Treatment with MEK inhibitors in KRAS mutant lung cancers lead to feedback activation of the MAPK pathway. In epithelial-like KRAS mutant lung cancers, this feedback was attributed to ERBB3-mediated re-activation of MEK. In contrast, in mesenchymal-like KRAS mutant lung cancers, the feedback was contributed to the fibroblast growth factor receptor 1 (FGFR1) pathway. Combination of MEK inhibitor trametinib with an FGFR inhibitor induced cell death in vitro in mesenchymal-like KRAS mutant cancers. These observations indicate that feedback activation of FGFR1 signaling mitigates the effect of MEK inhibitor in mesenchymal-like KRAS mutant lung tumors, and could establish a therapeutic approach to treat these cancers.

Free Research Field

腫瘍内科学