Monomerization of dimerized oncogenic fusion proteins by mimetic peptides as cancer treatments
| Project/Area Number |
18K15300
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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 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Asahikawa Medical College |
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Principal Investigator |
Hirai Noriko 旭川医科大学, 大学病院, 客員助教 (90596272)
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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 |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | がん / 肺がん / 遺伝子 / タンパク質 / 治療 / シグナル伝達 / 肺癌 / ドライバー遺伝子 / EML4 / ALK / ペプチド創薬 / RAS/RAF / 非小細胞肺癌 / ペプチド / 単量体 / 分子標的薬 / EML4-ALK / 蛋白多量体乖離 / 蛋白質相互作用 / EML4-ALK融合遺伝子 |
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| Outline of Final Research Achievements |
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (EML4-ALK) fusion accounts for 5% of non-small cell lung cancers (NSCLC). These oncogenic proteins are constitutively activated by dimerization via the coiled-coil (cc) domain. This gives us a question whether inhibition of the oncogenic protein dimerization could have an anti-cancer effect or not. This study investigated biological effects of cc mimetic molecules for ALK positive NSCLC cells.
In FKBP-mediated dimerization inducing model, we found cells expressing monomeric ALK did not grow both in vitro and vivo. Using a fluorescent system, we found overexpression of cc suppressed the fusion protein dimerization concomitant with decreasing the tumor growth. The treatment with synthesized cc peptides decreased the phosphorylation of ALK and suppressed the cell growth.
These findings suggested the monomerization of ALK fusion proteins could be a therapeutic strategy for ALK positive NSCLC.
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| Academic Significance and Societal Importance of the Research Achievements |
肺癌は国内罹患率・死亡率ともに高く、治療開発と予後改善は重要な課題である。非小細胞癌の5％にみられるEML4-ALK融合の発見後、ALKキナーゼ阻害を機序とした治療薬の開発が進んできた。それらは従来の殺細胞性抗癌剤と比較して劇的な生存期間の延長や毒性軽減によるQOLの改善をもたらしたが、長期投与により耐性化することが知られており、その克服が重要な課題である。本研究はその課題に対し「蛋白の多量体化に依存したがん」という全く新しい切り口からアプローチしたことに意義がある。また、多量体化による恒常的活性化は、臓器横断的に様々な腫瘍でみられ、将来重要な治療標的となる可能性を示したことに意義がある。
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Report
(5 results)
Research Products
(15 results)
