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

2020 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

腫瘍生物学

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。