Elucidation of mechanisms of xCT-mediated cancer therapy resistance accompanied with metabolic reprograming and cancer stem cell property

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02766
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Fujita Health University (2023); Keio University (2021-2022)
• Principal Investigator: Nagano Osamu 藤田医科大学, 腫瘍医学研究センター, 教授 (30404346)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: p62/SQSTM1 / xCT / 抗がん剤耐性 / オートファジー

Outline of Final Research Achievements

The initial standard treatment for small cell lung cancer (SCLC) is systemic chemotherapy with platinum drugs, but many patients experience relapse or disease progression. However, the mechanisms promoting resistance in relapsed/aggravated SCLC cells remain largely unknown. In this study, we demonstrated that the regulation of xCT expression via p62/SQSTM1 is involved in the progression of SCLC cells. Furthermore, we found that autophagy deficiency contributes to the cisplatin resistance of SCLC cells. Therefore, we searched for inhibitors to develop therapies targeting p62/SQSTM1 and identified promising candidates that can reduce the protein stability of p62/SQSTM1.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

小細胞肺癌（SCLC）の初回標準治療はプラチナ製剤併用全身化学療法であるが、その多くが再発・増悪をきたす。しかしながら、再発・増悪したSCLC細胞の治療抵抗性を促進するメカニズムについてはほとんど分かっていない。このようにアンメットメディカルニーズが高いがん腫におけてp62/SQSTM1を介した治療抵抗性メカニズムを明らかにし、新たな候補薬を同定した。この薬剤が臨床応用されれば、SCLCやp62/SQSTM1を高発現する高悪性度のがんに対して新たな治療法の開発に繋がることが期待でき、広く社会に貢献することが可能になる。