Systems analysis of intrinsic resistance to MEK inhibitor in KRas- or BRaf-mutataed cancer cells
| Project/Area Number |
26290053
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Okazaki Research Facilities, National Institutes of Natural Sciences (2016)
Kyoto University (2014-2015) |
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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)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2016: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2015: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2014: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
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| 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 / FRET / Akt / イメージング / レポーター |
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| 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.
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Report
(4 results)
Research Products
(21 results)
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[Journal Article] Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging.2016
Author(s)
Inaba K, Oda K, Aoki K, Sone K, Ikeda Y, Miyasaka A, Kashiyama T, Fukuda T, Makii C, Arimoto T, Wada-Hiraike O, Kawana K, Yano T, Osuga Y, Fujii T
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Journal Title
Oncotarget
Volume: 7
Pages: 29577-29591
DOI
NAID
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Variegated RHOA mutations in adult T-cell leukemia/lymphoma.2016
Author(s)
Nagata Y, Kontani K, Enami T, Kataoka K, Ishii R, Totoki Y, Kataoka TR, Hirata M, Aoki K, Nakano K, Kitanaka A, Sakata-Yanagimoto M, Egami S, Shiraishi Y, Chiba K, Tanaka H, Shiozawa Y, Yoshizato T, (9名), Miyano S, Nureki O, Shibata T, Haga H, Shimoda K, Katada T, Chiba S, Watanabe T, Ogawa S
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Journal Title
Blood.
Volume: 127
Pages: 596-604
DOI
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Synergistic antitumor effects of combination of PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging.2016
Author(s)
naba K, Oda K, Aoki K, Sone K, Ikeda Y, Miyasaka A, Kashiyama T, Fukuda T, Makii C, Arimoto T, Wada-Hiraike O, Kawana K, Yano T, Osuga Y, Fujii T.
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Journal Title
NAID
Related Report
Peer Reviewed
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