Systems analysis of intrinsic resistance to MEK inhibitor in KRas- or BRaf-mutataed cancer cells

2016 Fiscal Year Final Research Report

• Project/Area Number: 26290053
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Okazaki Research Facilities, National Institutes of Natural Sciences (2016); Kyoto University (2014-2015)
• Principal Investigator: AOKI Kazuhiro 大学共同利用機関法人自然科学研究機構(岡崎共通研究施設), 岡崎統合バイオサイエンスセンター, 教授 (80511427)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 内因的抵抗性 / FRETイメージング / 数理モデル / シミュレーション / KRas / BRaf / ERK / PI3K

Outline of Final Research Achievements

In this study, we analyzed molecular mechanisms of intrinsic resistance to MEK inhibitor in BRaf- or KRas-mutated cancer cells. In BRaf-mutated cancer cells, MEK inhibitor linearly reduced ERK activity and cell proliferation rate, whereas KRas-mutated cancer cells showed non-linear relation between ERK activity and cell proliferation induced by MEK inhibitor, thereby showing resistance to MEK inhibitor. This was mediated by mTOR pathway, and we confirmed that co-treatment with MEK inhibitor and PI3K/mTOR inhibitor synergistically decreased cell proliferation rate. The molecular mechanisms underlying mTOR-mediated intrinsic resistance to MEK inhibitor in KRas-mutant cancer cells were further analyzed by experiments and mathematical modeling. We found that not only feedback regulations between ERK and mTOR pathways but also transcriptional regulation by ERK pathway substantially contributed to the intrinsic resistance to MEK inhibitor.

Free Research Field

細胞生物学