| Project/Area Number |
15K09230
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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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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
高橋 史行 順天堂大学, 医学部, 准教授 (70327823)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 薬剤耐性 / 癌幹細胞 / 静止期 / 肺癌 / 非小細胞肺癌 / Gefitinib / EGFR-TKI耐性 / 肺癌幹細胞 / Gefitinib耐性 |
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| Outline of Final Research Achievements |
Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. In this study, we developed gefitinib-resistant persisters (GRPs) from two EGFR-mutant non-small cell lung cancer (NSCLC) cell lines, PC9 and HCC827 by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high level of lung CSC marker CD133 and gene X that is involved in the maintenance of quiescence of CSCs. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the gene X significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. These findings suggest that the maintenance of quiescence is important in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC.
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| Academic Significance and Societal Importance of the Research Achievements |
現在、肺癌は日本のみならず世界でも癌による死亡原因の第1位を占めている。とくに進行肺癌の予後は極めて不良であり、本研究によりGefitinib耐性機序における肺癌幹細胞の静止期維持機構の重要性が認識され、静止期制御分子の抑制や阻害剤を用いた癌幹細胞・静止期制御の有用性がより立証されれば、将来的に非小細胞肺癌におけるEGFR-TKI耐性克服の重要なオプションの一つとなり、進行肺癌の予後改善につながる可能性がある。
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