Development of an exosome-based biomarker for third-generation EGFR-TKI resistance

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16385
• 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: Osaka University
• Principal Investigator: Shintani Takuya 大阪大学, 医学部附属病院, 薬剤師 (40762076)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: miR-130a-3p / オシメルチニブ耐性 / EGFR-TKI / エクソソーム / 肺がん

Outline of Final Research Achievements

The acquisition of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is one of the major problems in lung cancer pharmacotherapy. Since the diagnosis of resistance requires patient-intensive tissue biopsy, we conducted this study to develop a new biomarker utilizing extracellular vesicles (EVs), which is useful for liquid biopsy. Using human EGFR mutation-positive lung cancer cells (PC9) and third-generation EGFR-TKI (osimertinib)-resistant cells (PC9OR), we found that PC9OR-EVs and EVs-miRNAs induced osimertinib resistance. Microarray analysis identified six miRNAs (miR-18a-5p, miR-20b-5p, miR-130a-3p, miR-378a-3p, miR-378f, and miR-424-3p) that were upregulated in PC9OR-EVs. We showed that miR-130a-3p was also upregulated in EVs derived from other resistant cells and induced osimertinib resistance. The pathway analysis suggested the involvement of TSC1/mTOR signaling as a mechanism. Our study is expected to contribute to the individualized medication of lung cancer.

Free Research Field

医療薬学

Academic Significance and Societal Importance of the Research Achievements

本研究で、新たにエクソソーム中miR-130a-3pが、複数のヒト肺がん細胞株においてオシメルチニブ耐性を誘導することを示した。エクソソーム中miRNAは、病態を表す低侵襲な診断ツールとして期待されている。がん細胞が放出するエクソソームは血中に移行し、全身を循環すると考えられており、血中のmiR-130a-3pはEGFR-TKIの薬効を予測する新規バイオマーカーとなりうる可能性があり、肺がん薬物療法の個別適正化・医療経済効果への波及も考えられる。また、miR-130a-3pを標的とした新規治療法の開発は、EGFR-TKI耐性の克服にも寄与する可能性もあり、今後の更なる研究の発展に期待される。