Analysis of mechanisms underlying homologous recombination deficiency induced by cancer metabolism inhibition

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07689
• 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: OKAMOTO Yuka 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 (50625217)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: がん / 解糖系 / グルタミン代謝 / 相同組換え修復

Outline of Final Research Achievements

Aberrant tumor metabolisms, such as enhanced glycolysis and glutaminolysis are distinctive metabolic features in solid tumors and can provide potential therapeutic targets. However, caner metabolisms exhibit high plasticity and are often hard to regulate by merely inhibiting a pathway. We have found that disruption of cancer metabolism can lead to cisplatin sensitization with DNA double strand breaks (DSB) accumulation in certain cancer cell lines. Therefore, in this research, the mechanisms of such homologous recombination deficiency-like phenotype induced by inhibition of glutaminolysis was assessed for therapeutical application of this synthetic lethality.

Free Research Field

腫瘍治療学

Academic Significance and Societal Importance of the Research Achievements

本研究で用いた、グルタミナーゼ(GLS)阻害薬は、固形がんを中心に臨床試験が実施され、臨床開発が試みられている。興味深いことに、申請者らの検討から、このGLS阻害薬が、固形がんで広く用いられる抗がん剤シスプラチンの感受性化を細胞選択的に誘導することが明らかとなった。また、合成致死効果への感受性の規定因子候補として、特定の遺伝子発現や遺伝子依存性を見出した。本研究による成果は、GLS阻害薬や代謝阻害薬の臨床開発に有用な新たな知見をもたらすものであったと考えられる。