Elucidation of the mechanism underlying tumor initiation via DNA replication stress regulated by ATR
| Project/Area Number |
18H03378
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 63020:Radiation influence-related
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| Research Institution | National Cancer Center Japan |
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Principal Investigator |
Shiotani Bunsyo 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (10627665)
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| Co-Investigator(Kenkyū-buntansha) |
足立 淳 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 創薬デザイン研究センター, プロジェクトリーダー (20437255)
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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 |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
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| Keywords | ATR / DNA replication stress / genome instability / KRAS / Lung cancer / DNA複製ストレス / 発がん機構 / 癌遺伝子 / ゲノム不安定性 |
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| Outline of Final Research Achievements |
In this study, we revealed that ATR plays an important role in DNA replication stress tolerance and the acquisition of malignant phenotype by mutant KRASG12V in lung epithelial cells. In the presence of increased ATR expression, the slowed replication fork progression under KRASG12V-induced acute and chronic RS is unrestrained by an ATR kinase-dependent regulation of DNA replication stress tolerance candidate factors, which function as regulatory modules in the replication fork and complete replication. These mechanisms support cell survival but at the same time promote genomic instability leading to cell malignancy. These findings hold promise for the development of novel therapies using ATR inhibitors for patients with mutant KRAS lung cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によって得られた、ATR制御する変異型KRASG12V によるDNA複製ストレス耐性による細胞生存とゲノム不安定性を伴う肺上皮細胞のがん悪性化形質獲得機構は、非遺伝性がんにおけるDNA修復因子の変異によらない高頻度ながんゲノム不安定性が、ATR依存的なDNA複製ストレス抵抗性によってもたらされることを示し、ATRの腫瘍促進因子としての学術的意義を明らかとした。またこの成果は変異型KRAS肺がん患者におけるATRシグナル経路を標的とする新規抗がん治療の開発に貢献することが期待される。
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Report
(4 results)
Research Products
(19 results)
