Clinical application and biomarker of CHK1 inhibitor-mediated cell death
| Project/Area Number |
18K07246
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Research Institute for Clinical Oncology Saitama Cancer Center (2020-2021)
Showa University (2018-2019) |
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Principal Investigator |
Ando Kiyohiro 地方独立行政法人埼玉県立病院機構埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 副部長 (10455389)
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| Co-Investigator(Kenkyū-buntansha) |
末永 雄介 千葉県がんセンター(研究所), 発がん研究グループ 発がん制御研究部, 研究員 (80581793)
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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 |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | CHK1阻害剤 / 神経芽腫 / DNA損傷応答 / CEP131 / FGFR2 / MEK阻害剤 / DNA-PK阻害剤 / MYCN / DNA損傷修復 / CHK1 / MEK / ERK / neuroblastoma / kinase inhibitor / FGFR２ / ATM / DNA-PK / p63 / CHP134 / 10q loss / checkpoint kinase 1 |
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| Outline of Final Research Achievements |
Selective inhibitors of checkpoint kinase 1 (CHK1) are undergoing clinical evaluation for various human malignancies. We reported that ATM inhibitor and DNA-PK inhibitor potentiated CHK1 inhibitor-mediated cell death in neuroblastoma cell line. Furthermore, the decreased expression of fibroblast growth factor receptor 2 (FGFR2) was causally related to CHK1 sensitivity. Since FGFR2 activated MEK/ERK pathway for cell proliferation, our data suggested that loss of FGFR2 expression might be possible utilization for determination of CHK1 inhibitor sensitivity in patients with neuroblastoma, whereas the increase expression of FGFR2 might be a candidate biomarker for combination therapy with MEK inhibitor.
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| Academic Significance and Societal Importance of the Research Achievements |
CHK1阻害剤は、非臨床において高い抗腫瘍効果が示されているにもかかわらず、臨床試験の結果はいまだ十分でないことから、治療応用には感受性遺伝子の同定が急務である。本研究では、CHK1の機能阻害に対してATMまたはDNA-PKのDNA損傷修復機構及びFGFR2の細胞増殖効果が補完的に働くことが明らかとなった。この成果は、がん細胞におけるCHK1の機能的役割に新しい知見を与える学術的意義が高いと考えられ、またこれらの感受性に関連するがん細胞の遺伝子背景は、効果予測および適応決定の指標として今後の適切なCHK1阻害剤の臨床試験デザインに有用であり、また併用治療薬の選択に臨床的意義が高いと考える。
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Report
(5 results)
Research Products
(8 results)
