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

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• 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 / 酸化ストレス

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.

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。

Research Products

• [Journal Article] Vasodilator oxyfedrine inhibits aldehyde metabolism and thereby sensitizes cancer cells to xCT-targeted therapy. (2020)
  • Author(s): Otsuki Y, Yamasaki J, Suina K, Okazaki S, Koike N, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 111 Issue: 1 Pages: 127-136
  • DOI: 10.1111/cas.14224
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma. (2019)
  • Author(s): Okazaki S, Umene K, Yamasaki J, Suina K, Otsuki Y, Yoshikawa M, Minami Y, Masuko T, Kawaguchi S, Nakayama H, Banno K, Aoki D, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 110 Issue: 11 Pages: 3453-3463
  • DOI: 10.1111/cas.14182
  • Peer Reviewed / Open Access
• [Journal Article] EGFR promotes glioma progression by regulating xCT and GluN2B-containing NMDA receptor signaling. (2018)
  • Author(s): Suina K, Tsuchihashi K, Yamasaki J, Kamenori S, Shintani S, Hirata Y, Okazaki S, Sampetrean O, Baba E, Akashi K, Takahashi F, Takahashi K, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3874-3882
  • DOI: 10.1111/cas.13826
  • Peer Reviewed / Open Access
• [Journal Article] Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells (2018)
  • Author(s): Okazaki Shogo、Shintani Subaru、Hirata Yuki、Suina Kentaro、Semba Takashi、Yamasaki Juntaro、Umene Kiyoko、Ishikawa Miyuki、Saya Hideyuki、Nagano Osamu
  • Journal Title: Oncotarget Volume: 9 Issue: 73 Pages: 33832-33843
  • DOI: 10.18632/oncotarget.26112
  • Peer Reviewed / Open Access
• [Journal Article] Development of a functional thyroid model based on an organoid culture system. (2018)
  • Author(s): Saito Y, Onishi N, Takami H, Seishima R, Inoue H, Hirata Y, Kameyama K, Tsuchihashi K, Sugihara E, Uchino S, Ito K, Kawakubo H, Takeuchi H, Kitagawa Y, Saya H, Nagano O.
  • Journal Title: Biochem Biophys Res Commun Volume: 497 Issue: 2 Pages: 783-789
  • DOI: 10.1016/j.bbrc.2018.02.154
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] xCT阻害剤抵抗性を示す癌細胞に対してxCT阻害剤と合成致死を誘導する薬剤の同定 (2019)
  • Author(s): 永野 修
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 癌細胞に鉄依存性細胞死を誘導するxCT標的治療とその抵抗性を克服する薬剤の探索 (2018)
  • Author(s): 永野修
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Cancer treatment strategy targeting antioxidant system potentiated by CD44v-xCT in stem-like cancer cells. (2017)
  • Author(s): Osamu Nagano
  • Organizer: 10th international BioMedical Transporters Conference
  • Int'l Joint Research / Invited