Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers
Copyright policy )Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers
Significance Mammalian SWI/SNF (mSWI/SNF) alterations are highly prevalent, now estimated to occur in 20% of cancers. The inactivating nature of mSWI/SNF mutations presents a challenge for devising strategies to target these epigenetic lesions. By performing a comprehensive pooled shRNA screen of the epigenome using a unique deep coverage design shRNA (DECODER) library across a large cancer cell line panel, we identified that BRG1/SMARCA4 mutant cancer cells are highly sensitive to BRM/SMARCA2 depletion. Our study provides important mechanistic insight into the BRM/BRG1 synthetic lethal relationship, shows this finding translates in vivo, and highlights BRM as a promising therapeutic target for the treatment BRG1 -mutant cancers.
- Dana-Farber Cancer Institute United States
- Novartis (Netherlands) Netherlands
- Harvard University United States
- Novartis (Switzerland) Switzerland
Blotting, Western, DNA Helicases, Nuclear Proteins, Cell Cycle Checkpoints, Epigenesis, Genetic, Histones, Cell Line, Tumor, Gene Knockdown Techniques, Multiprotein Complexes, Neoplasms, Humans, Immunoprecipitation, RNA, Small Interfering, Cellular Senescence, Gene Library, Transcription Factors
Blotting, Western, DNA Helicases, Nuclear Proteins, Cell Cycle Checkpoints, Epigenesis, Genetic, Histones, Cell Line, Tumor, Gene Knockdown Techniques, Multiprotein Complexes, Neoplasms, Humans, Immunoprecipitation, RNA, Small Interfering, Cellular Senescence, Gene Library, Transcription Factors
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