Elucidating molecular mechanisms of anti-cancer drug resistance of EGFR mutation-positive lung cancer by using single-cell technology

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16370
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: SETO Yosuke 公益財団法人がん研究会, がん化学療法センター 基礎研究部, 研究員 (50738614)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: シングルセル解析 / 薬剤耐性 / 肺がん

Outline of Final Research Achievements

EGFR molecular-targeted drugs (EGFR-Tyrosine Kinase Inhibitor (TKI)) are treated for activating EGFR mutation-positive non-small cell lung cancers (NSCLCs). However, acquired resistance after initial clinical response is widely observed. To elucidate mechanisms of emergence of the drug resistance against EGFR-TKI, we conducted single-cell (sc) RNA-seq, scATAC-seq using EGFR mutation-positive NSCLC patient-derived cancer cells (PDCs). In this study, we found that NF-kappa B mediated inflammatory response may play an important role in survival under EGFR-TKI treatment. We further found tumor heterogeneity in the PDC populations and T790M resistance mutation-positive PDC-specific nucleotide substitution pattern (e.g. higher C-to-T mutation). These results suggested that the mutational pattern was changed during the process of the emergence of drug-resistance mutation.

Free Research Field

分子進化

Academic Significance and Societal Importance of the Research Achievements

肺がんにおける分子標的薬を用いた治療は劇的な治療効果をもたらすが、治療数年内に薬剤耐性変異の出現がおこることが臨床上大きな問題となっている。しかしながら、耐性変異獲得に至るがん進化メカニズムはほとんど明らかとなっていない。本研究により、治療前がん細胞集団から薬剤耐性変異獲得の過程で塩基置換パターンが変化することやその変化にかかわる可能性のある遺伝子の発現、さらに、耐性変異獲得前のがん細胞では、薬剤存在下での生存に炎症応答が関与していること示唆され、がん進化プロセスを理解する上で重要な知見を得た。