Elucidation of the mechanism of gene amplification as drug resistance and its clinical application.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15581
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kobayashi Yoshihisa 国立研究開発法人国立がん研究センター, 研究所, 研究員 (30734628)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: EGFR / 薬剤耐性 / 融合遺伝子

Outline of Final Research Achievements

EGFR mutant lung adenocarcinomas respond to EGFR inhibitors, but eventually develop resistance. In this study, we applied CRISPR-Cas9 genome editing technology to investigate drug resistance. We created various fusion gene models through genome editing and confirmed their function as mechanisms of drug resistance. We identified therapeutic agents to overcome resistance caused by fusion genes and further discovered that cancer acquires various gene amplifications against this treatment (Kobayashi et al., Nature Communications 2022). These findings provide valuable models and foundational data for ongoing research on fusion and gene amplifications.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

肺がんは最も死亡者数の多いがん種で、日本だけで年間7万人以上にのぼる。EGFR遺伝子変異は日本人肺腺がんの半数にみられ、このタイプにはEGFR阻害剤が標準治療となっているが、次第に耐性を獲得することが問題である。本研究成果は、融合遺伝子によって薬剤耐性となった患者に有効な新たな治療戦略の開発に有用である。また、融合遺伝子・遺伝子増幅に関する今後の生物学的な研究への貢献も期待できる。