Elucidation of the mechanism of the induction of ferroptosis by xCT inhibitor and its antitumor effect in small cell lung cancer

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03583
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Keio University
• Principal Investigator: Nagano Osamu 慶應義塾大学, 医学部(信濃町), 准教授 (30404346)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: フェロトーシス / 癌 / xCT / 小細胞肺癌 / グルタチオン / 活性酸素種

Outline of Final Research Achievements

In this study, we investigated the susceptibility of small cell lung cancer (SCLC) to ferroptosis. We identified SLC7A1 (xCT), SLC3A2 (CD98hc), MALT1 and BIRC3 as the markers that were downregulated in SCLC and correlated with susceptibility to ferroptosis. Furthermore, we performed immunostaining of xCT using a human lung cancer tissue sample and confirmed that xCT expression was low in SCLC. The tumor organoids were prepared from the RPM mouse, an animal model of SCLC, to establish a model to evaluate the impact of ferroptosis-inducing cancer therapy. Finally, we conducted a non-clinical study by using the xCT inhibitor and obtained a POC in which the ferroptosis-inducing therapy is effective treatment for SCLC.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

進展型SCLCの標準治療は10年以上変化がなく、その治療開発はアンメットメディカルニーズが非常に高い領域であった。しかしながら本研究により、小細胞肺癌に対してxCT阻害剤を使用したフェロトーシス誘導療法が有効であることを明らかにし、xCT阻害剤を使用するためのPOCを取得することができた。今後、xCT阻害剤を用いた臨床試験へと移行するための基盤を整備することができるようになった。