Analysis on the mechanisms of plasticity and maintenance of gastric cancer drug-tolerant persister cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07251
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: MASHIMA Tetsuo 公益財団法人がん研究会, がん化学療法センター 分子生物治療研究部, 主任研究員 (30311228)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ALDH / 胃がん / BET阻害剤 / Persister細胞

Outline of Final Research Achievements

We found that aldehyde dehydrogenase 1 family member A3 (ALDH1A3) was up-regulated by anticancer drugs in gastric cancer patient-derived cells and was involved in tumor growth. Gastric cancer tissues treated with neoadjuvant chemotherapy showed high ALDH1A3 expression. Histone H3K27acetylation increased in the ALDH1A3 promoter in gastric cancer chemotherapeutic drug-tolerant persister (DTP) cells. Among the BET proteins, BRD4 was specifically recruited to the ALDH1A3 promoter in the DTP cells. Importantly, combination therapy with anticancer drug and BET inhibitor significantly suppressed ALDH1A3 expression and inhibited tumor growth. These data suggest that BET inhibitors target DTP cells in gastric cancer. (Collaborator: Lee Jin)

Free Research Field

腫瘍薬物応答学

Academic Significance and Societal Importance of the Research Achievements

本研究により、BETタンパク質の働きを介した生存因子ALDH1A3の発現誘導が、胃がんの薬物療法において、薬物療法初期に生じる治療抵抗性に関わることが示された。本研究結果は、がん細胞の可塑性が薬剤耐性に関わることを立証するという観点で、病態生物学領域での基礎研究成果としての意義がある。また現在、内外で臨床開発が進められているBET阻害剤がどのような臨床の局面で有効性を示すかに関し、新たな基盤データを提示するものである。特に本研究は、胃がんの治療抵抗性克服のための新しい方法を示す成果としての意義を持つ。