Molecular basis of oncogenic mutation-associated resistance to endoplasmic reticulum stresses and their applications to cancer chemotherapy

• Project/Area Number: 18K07309
• 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: KUNIMASA Kazuhiro 公益財団法人がん研究会, がん化学療法センター ゲノム研究部, 研究員 (50534020)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 小胞体ストレス応答 / がん遺伝子 / 活性化変異 / がん微小環境 / 小胞体ストレス / 小胞体ストレス抵抗性

Outline of Final Research Achievements

Tumor microenvironment is clinical circumstances where endoplasmic reticulum (ER) stresses tend to accumulate. Acquired resistance to ER stresses is one of key steps during cancer progression. In this study, we found that oncogenic mutations of gene “X” render resistance to ER stresses via suppression of ER stress-induced Bim, a proapoptotic Bcl-2 family protein. Furthermore, we carried out a phenotypic screening for compounds with the ability to cancel resistance to ER stresses and fount that exportin-1 inhibitors can overcome the resistance.

Academic Significance and Societal Importance of the Research Achievements

小胞体ストレス抵抗性化機序の解明とそれに対する阻害剤の同定は、がん遺伝子Xの増殖シグナル阻害とは異なる作用機序に基づいたがん治療法の確立やX活性化変異がんに特徴的な病態の理解に繋がることが期待される。各種活性型がん遺伝子特有のストレス適応機構を明らかにできつつあり、今後の治療標的化研究への展開に重要な示唆を与えるデータが得られたと考えている。

Research Products

• [Journal Article] GZD824 Inhibits GCN2 and Sensitizes Cancer Cells to Amino Acid Starvation Stress (2020)
  • Author(s): Kato Yu、Kunimasa Kazuhiro、Takahashi Mizuki、Harada Ayaka、Nagasawa Ikuko、Osawa Masanori、Sugimoto Yoshikazu、Tomida Akihiro
  • Journal Title: Molecular Pharmacology Volume: 98 Issue: 6 Pages: 669-676
  • DOI: 10.1124/molpharm.120.000070
  • Peer Reviewed
• [Journal Article] Disrupting ATF4 Expression Mechanisms Provides an Effective Strategy for BRAF-Targeted Melanoma Therapy (2020)
  • Author(s): Nagasawa Ikuko、Koido Masaru、Tani Yuri、Tsukahara Satomi、Kunimasa Kazuhiro、Tomida Akihiro
  • Journal Title: iScience Volume: 23 Issue: 4 Pages: 101028-101028
  • DOI: 10.1016/j.isci.2020.101028
  • Peer Reviewed / Open Access
• [Journal Article] BCR-ABL tyrosine kinase inhibition induces metabolic vulnerability by preventing the integrated stress response in K562 cells. (2018)
  • Author(s): Kato Y, Kunimasa K, Sugimoto Y, Tomida A.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 504 Issue: 4 Pages: 721-726
  • DOI: 10.1016/j.bbrc.2018.09.032
  • Peer Reviewed
• [Presentation] 1.Inhibitory effects of mubritinib, a novel UPR inhibitor, on mitochondrial respiratory chain (2020)
  • Author(s): 國政和宏, 塚原里美, 冨田章弘
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 膵がん細胞株におけるグルコース飢餓下でのミトコンドリア機能の重要性 (2018)
  • Author(s): 國政和宏、冨田章弘
  • Organizer: 第22回日本がん分子標的治療学会学術集会
• [Presentation] ミトコンドリア機能はグルコース飢餓下での膵がん細胞の生存に必須である (2018)
  • Author(s): 國政和宏、塚原里美、冨田章弘
  • Organizer: 第77回日本癌学会学術総会
• [Remarks]
  • URL: https://www.jfcr.or.jp/chemotherapy/department/genome/index.html