Elucidation of the combination effects of HDAC inhibitors and IMiDs

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16314
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Asatsuma Tomoko 東京医科大学, 医学部, 助教 (70732303)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: HDAC阻害剤 / 多発性骨髄腫 / IMiDs / CRBN / セレブロン / HDAC

Outline of Final Research Achievements

Combined usage of immunomodulatory drugs (IMiDs) and histone deacetylase (HDAC) inhibitors provides beneficial therapeutic effects in multiple myeloma, but the specific molecular mechanisms underlying the combination of these drugs remain unclear. In this study, we focused on KEY, an IMiDs-specific CRL4CRBN degradation substrate and an essential factor for multiple myeloma survival, that is further reduced by the addition of HDAC inhibitors, and identified HDACs and their downstream molecular pathways involved in KEY reduction.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

IMiDsの抗多発性骨髄腫作用を担うCRBNの存在が明らかになってからは、その作用の中核を担うようなIMiDs依存的なCRL4CRBNの分解基質が解明されてきた一方で、他の薬剤との併用効果の分子機構については、解明が遅れている。今回、IMiDsとHDAC阻害剤の併用における下流経路の一端が明らかとなった。これらを標的としたHDAC阻害剤やIMiDsの新たなプロトコール改善や適応拡大、また、応用的な後続研究の礎となりえる。