Optimization of treatment strategy with EZH2 inhibitor for solid cancer with SWI/SNF alteration

• Project/Area Number: 20K07691
• 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: Hokkaido University
• Principal Investigator: Kinoshita Ichiro 北海道大学, 大学病院, 教授 (40343008)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: エピジェネティクス / SWI/SNF / SMARCA4 / HDAC inhibitor / CDK4/6 inhibitor / MTOR / everolimus / EZH2 / 固形がん / Everolimus / KDM5 / HDAC / CDK4/6

Outline of Research at the Start

クロマチンリモデリングを担うSWI/SNF複合体のサブユニットの変異・欠失が固形腫瘍全体で20%を占めることが明らかとなった。SWI/SNFはヒストン修飾酵素EZH2とエピジェネティックな拮抗作用を有しており、SWI/SNFの異常がEZH2阻害薬のバイオマーカーとなる可能性がある。本研究では、SWI/SNFが、他のヒストン修飾酵素KDM5に対しても、エピジェネティックな拮抗作用を有しているとの仮説を立て、SWI/SNF異常を有する細胞に対するEZH2阻害薬とKDM5阻害薬の併用効果を検討する。さらに、SWI/SNFサブユニット変異のバイオマーカーとしての意義を検討する。

Outline of Final Research Achievements

The efficacy of epigenetics-targeted therapy with HDAC inhibitors was synergistically enhanced in combination with CDK4/6 inhibitors in lung cancer cells, mainly those with SWI/SNF abnormalities. We identified candidate effector molecules highly expressed in cells showing synergistic effects of the combination therapy. In addition, lung cancer cells with mutant SMARCA4, a major component of SWI/SNF, showed clonal growth ability dependent on the MTOR pathway and high growth inhibition by MTOR inhibitors.

Academic Significance and Societal Importance of the Research Achievements

EZH2阻害薬を含むエピジェネティクスを標的とした治療の固形腫瘍における有効性は限定的である。本研究では、固形腫瘍全体で20%を占めるエピジェネティクス関連因子SWI/SNF複合体に着目して、エピジェネティクス治療の改善を目指した。SWI/SNFの異常を有する固形腫瘍を主体として、HDAC阻害薬によるエピジェネティクス標的治療の効果が、CDK4/6阻害薬との併用で、相乗的に増強する可能性が示唆された。また、SWI/SNFの主要構成因子であるSMARCA4変異陽性腫瘍において、MTOR阻害薬の治療効果が高く、エピジェネティクスを標的とする治療との併用薬の候補となる可能性が示唆された。

Research Products

• [Journal Article] EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment. (2023)
  • Author(s): Shiiya A, Noguchi T, Tomaru U, Ariga S, Takashima Y, Ohhara Y, Taguchi J, Takeuchi S, Shimizu Y, Kinoshita I, Koizumi T, Matsuno Y, Shinagawa N, Sakakibara-Konishi J, Dosaka-Akita H
  • Journal Title: Cancer Sci Volume: 114 Issue: 4 Pages: 1270-1283
  • DOI: 10.1111/cas.15701
  • Peer Reviewed / Open Access
• [Journal Article] Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study (2022)
  • Author(s): Takada Kohichi、Kubo Tomohiro、Kikuchi Junko
  • Journal Title: Frontiers in Oncology Volume: 12 Pages: 99-99
  • DOI: 10.3389/fonc.2022.988527
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacokinetics, safety, and efficacy of trastuzumab deruxtecan with concomitant ritonavir or itraconazole in patients with HER2-expressing advanced solid tumors (2021)
  • Author(s): Takahashi S, Karayama M, Takahashi M, Watanabe J, Minami H, Yamamoto N, Kinoshita I, Lin CC, Im YH, Achiwa I, Kamiyama E, Okuda Y, Lee C, Bang YJ
  • Journal Title: Clin Cancer Res Volume: 27 Issue: 21 Pages: 5771-5780
  • DOI: 10.1158/1078-0432.ccr-21-1560
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer (2021)
  • Author(s): Hagio K, Amano T, Hayashi H, Takeshita T, Oshino T, Kikuchi J, Ohhara Y, Yabe I, Kinoshita I, Nishihara H, Yamashita H
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 8109-8109
  • DOI: 10.1038/s41598-021-87645-6
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of comprehensive genomic profiling tests covered by public insurance in patients with advanced solid cancers in Hokkaido, Japan (2021)
  • Author(s): Kikuchi Junko、Ohhara Yoshihito、Takada Kohichi、Kinoshita Ichiro
  • Journal Title: Japanese Journal of Clinical Oncology Volume: - Issue: 5 Pages: 753-761
  • DOI: 10.1093/jjco/hyaa277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of the immunoproteasome subunit β5i in non-small cell lung carcinomas (2020)
  • Author(s): Kiuchi Takayuki、Tomaru Utano、Ishizu Akihiro、Imagawa Makoto、Iwasaki Sari、Suzuki Akira、Otsuka Noriyuki、Ohhara Yoshihito、Kinoshita Ichiro、Matsuno Yoshihiro、Dosaka-Akita Hirotoshi、Kasahara Masanori
  • Journal Title: Journal of Clinical Pathology Volume: 74 Issue: 5 Pages: 300-306
  • DOI: 10.1136/jclinpath-2020-206618
  • Peer Reviewed
• [Journal Article] Clinical impact of a cancer genomic profiling test using an in‐house comprehensive targeted sequencing system (2020)
  • Author(s): Hayashi Hideyuki、Tanishima Shigeki、Fujii Kyoko、Mori Ryo、Okada Chihiro、Yanagita Emmy、Shibata Yuka、Matsuoka Ryosuke、Amano Toraji、Yamada Takahiro、Yabe Ichiro、Kinoshita Ichiro、Komatsu Yoshito、Dosaka‐Akita Hirotoshi、Nishihara Hiroshi
  • Journal Title: Cancer Science Volume: 111 Issue: 10 Pages: 3926-3937
  • DOI: 10.1111/cas.14608
  • Peer Reviewed / Open Access
• [Presentation] TRK融合陽性の消化器がん患者におけるラロトレクチニブの長期有効性と安全性 (2022)
  • Author(s): 木下 一郎, Garralda Elena, Hong David S., Xu Ruihua, Deeken John, Italiano Antonine, Liu Tianshu, Calvo Ferrandiz Aitana, Patel Jyoti D., Lee Dae Ho, Norenberg Ricarda, Burcoveanu Domnita-Ileana, Mussi Chiara E., Drilon Alexander, Shen Li
  • Organizer: 第60会日本癌治療学会学術集会
• [Presentation] TRK融合陽性の消化器がん患者におけるラロトレクチニブの有効性と安全性 (2021)
  • Author(s): 木下 一郎, Boni Valentina, Drilon Alexander, Deeken John F., Cabanas Elena G., Chung Hyun C., Oh Do-Youn, Patel Jyoti D., Xu Ruihua, Norenberg Ricarda, Brega Nicoletta, Dima Laura, Hong David S., Berlin Jordan
  • Organizer: 第59回日本癌治療学会学術集会
• [Presentation] CGP 検査前後の患者に対する意思決定支援（がんゲノム医療中核拠点病院） (2021)
  • Author(s): 木下一郎
  • Organizer: 第6 回日本がんサポーティブケア学会学術集会
  • Invited
• [Presentation] Clinical sequencing with insurance-covered genomic profiling tests in patients with advanced solid cancers in Hokkaido (2021)
  • Author(s): Junko Kikuchi, ‥, Ichiro Kinoshita
  • Organizer: 18th Annual Meeting of Japanese Society of Medical Oncology