Understanding metabolic impacts by IDH mutations and validating the efficacy of therapeutic targeting of BCAT1

2019 Fiscal Year Final Research Report

• Project/Area Number: 19K21334
• Project/Area Number (Other): 18H06235 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: National Cancer Center Japan
• Principal Investigator: Hattori Ayuna 国立研究開発法人国立がん研究センター, 研究所, 研究員 (60820420)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Keywords: がん代謝 / 白血病 / アミノ酸

Outline of Final Research Achievements

Mutations in IDHs are frequently found in malignant tumors. The mutant IDH (mIDH) lost its normal enzymatic activity and instead gained a new function of catalyzing the conversion of α-KG to D-2-hydroxyglutarate(2-HG). Due to the cancer-specific expression of mIDH, it is regarded as an ideal therapeutic target. However, it is still unclear how IDH mutations maintain tumors. Recent studies have demonstrated that 2-HG not only inhibit many types of αKG-dependent enzymes. In this study, we identified BCAT1 as a novel target of 2-HG. BCAT1 encodes an intracellular aminotransferase for the branched-chain amino acids (BCAAs). We have recently shown that BCAT1 is functionally essential for leukemia stem cell maintenance. That is, by inhibiting BCAT1, 2-HG has an important aspect of inhibiting cancer growth.

Free Research Field

腫瘍分子生物学

Academic Significance and Societal Importance of the Research Achievements

難治性がんに共通して見つかるイソクエン酸脱水素酵素IDH遺伝子変異は、がん細胞特異的に変異型IDH (mutIDH)タンパク質を発現させることから、有効な治療標的である。しかし、実際のIDH阻害薬を用いた治療では再発の問題が残る。今回、2-HGの標的因子として新たにがん促進因子であるBCAT1を同定した。今後、IDH阻害薬使用時にBCAT1再活性化が引き起こされるか調べることで、再発を防ぐ治療戦略に繋がることが期待される。