Drug discovery based on collateral lethality

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19586
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Takahashi Chiaki 金沢大学, がん進展制御研究所, 教授 (50283619)
• Research Collaborator: Kohno Susumu
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: がん / 代謝 / SUCLA2 / 合成致死性

Outline of Final Research Achievements

Initially, we thought that inhibition of SUCLG2, which is an isozyme of SUCLA2, exerts synthetic lethality, but the effect was limited. Therefore, we created a prostate cancer cell line lacking SUCLA2 and a prostate cancer cell line in which SUCLA2 was reconstituted. Using the CRISPR-CAS9 library, we searched genes those dropped specifically in prostate cancer cell lines lacking SUCLA2, and obtained 8 candidate genes. Furthermore, we screened for compounds that induce cell death specifically in SUCLA2-deficient prostate cancer, and to date, from the screening of natural compound libraries, we found two compounds are specifically cytotoxic for SUCLA2-deleted strains.

Free Research Field

腫瘍学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

RB遺伝子の近傍に位置するSUCLA2が、RB遺伝子領域の欠失に極めて頻繁に巻き込まれることが判った。SUCLA2は重要な代謝酵素をコードするので、この遺伝子欠損と合成致死性を示す標的分子を探索した。遺伝子欠損が合成致死性を発揮する遺伝子を８種、その作用が合成致死性を発揮する化合物２種を特定した。特定のゲノム異常を持つがんを標的にする副作用の少ない薬剤の開発につながると思われる。