| Project/Area Number |
18K15238
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Shinshu University |
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Principal Investigator |
Kitazawa Masato 信州大学, 学術研究院医学系(医学部附属病院), 講師 (10467152)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 大腸癌 / KRAS / MEK / BCL-XL / KRAS変異 / MEK阻害剤 / BCL-XL阻害剤 / KRAS遺伝子変異 / 個別化治療 |
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| Outline of Final Research Achievements |
Mutant KRAS is strongly implicated in carcinogenesis, proliferation, invasion, and metastasis, but targeted therapeutics against it have not yet been found. We established Mix culture assay that can screen effective drugs for KRAS-mutant colorectal cancer in vitro. Our study demonstrated that (1) KRAS-mutant colorectal cancer cells are sensitive to MEK inhibitors, (2) MEK inhibitors induce expression of the anti-apoptotic protein BCL-XL, and (3) the combination of MEK inhibitors and BCL-XL inhibitors can be a more selective molecular targeted therapy. Furthermore, we demonstrated that the combination of MEK inhibitor and BCL-XL inhibitor is effective for KRAS-mutant colorectal cancer in vivo.
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| Academic Significance and Societal Importance of the Research Achievements |
KRAS変異は最も重要な遺伝子変異であるが、今までそれに対する有効な治療方法は確立されていないかった。本研究によりKRAS変異大腸癌に対してMEK阻害剤とBCL-XL阻害剤のコンビネーション治療が有効である可能性が示唆された（Int J Oncol.2020;57:1179-91）。 またKRAS変異G12C大腸癌に新規薬剤AMG510とMEK阻害の2剤併用、さらにはBCL-XL阻害剤を加えた3剤併用の効果を細胞実験で証明し報告した(Mol Clin Oncol. 2021;15:148.)。本研究により予後不良であったKRAS変異癌に対する有効な治療戦略が確立されることが期待される。
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