Abstract
Large-scale cancer genome sequencing studies have revealed that chromatin regulators are frequently mutated in cancer. In particular, more than 20% of cancers harbour mutations in genes that encode subunits of SWI/SNF (BAF) chromatin remodelling complexes. Additional links of SWI/SNF complexes to disease have emerged with the findings that some oncogenes drive transformation by co-opting SWI/SNF function and that germline mutations in select SWI/SNF subunits are the basis of several neurodevelopmental disorders. Other chromatin remodellers, including members of the ISWI, CHD and INO80/SWR complexes, have also been linked to cancer and developmental disorders. Consequently, therapeutic manipulation of SWI/SNF and other remodelling complexes has become of great interest, and drugs that target SWI/SNF subunits have entered clinical trials. Genome-wide perturbation screens in cancer cell lines with SWI/SNF mutations have identified additional synthetic lethal targets and led to further compounds in clinical trials, including one that has progressed to FDA approval. Here, we review the progress in understanding the structure and function of SWI/SNF and other chromatin remodelling complexes, mechanisms by which SWI/SNF mutations cause cancer and neurological diseases, vulnerabilities that arise because of these mutations and efforts to target SWI/SNF complexes and synthetic lethal targets for therapeutic benefit.
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Acknowledgements
The authors thank the National Cancer Institute (NCI) for their funding support (R01 CA113794, R01 CA172152 and R01 CA273455 to C.W.M.R.). The work of C.W.M.R. is also supported by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital (SJCRH), including funding from the SJCRH Collaborative Research Consortium on Chromatin Regulation in Paediatric Cancer, and grants from Cure AT/RT Now, the Avalanna Fund and the Garrett B. Smith Foundation. H.A.M. is supported by the St. Jude Graduate School of Biomedical Sciences and the Ruth L. Kirschstein National Research Service Award (F31 CA278355). The authors thank members of the Roberts lab, A. Durbin (SJCRH) and E. Wickman (SJCRH) for insightful discussions and V. Shanker (SJCRH) for scientific editing of the manuscript.
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Malone, H.A., Roberts, C.W.M. Chromatin remodellers as therapeutic targets. Nat Rev Drug Discov 23, 661–681 (2024). https://doi.org/10.1038/s41573-024-00978-5
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DOI: https://doi.org/10.1038/s41573-024-00978-5
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