大规模癌症基因组测序研究表明，染色质调节因子在癌症中经常发生突变。特别是，超过 20% 的癌症存在编码 SWI/SNF (BAF) 染色质重塑复合物亚基的基因突变。研究发现，一些癌基因通过选择 SWI/SNF 功能来驱动转化，并且某些 SWI/SNF 亚基中的种系突变是几种神经发育障碍的基础，因此出现了 SWI/SNF 复合物与疾病的其他联系。其他染色质重塑因子，包括 ISWI、CHD 和 INO80/SWR 复合体的成员，也与癌症和发育障碍有关。因此，SWI/SNF 和其他重塑复合物的治疗操作引起了极大的兴趣，针对 SWI/SNF 亚基的药物已进入临床试验。对具有 SWI/SNF 突变的癌细胞系进行全基因组扰动筛选已确定了其他合成致死靶标，并导致进一步的化合物进入临床试验，其中一种已获得 FDA 批准。在这里，我们回顾了了解 SWI/SNF 和其他染色质重塑复合物的结构和功能的进展、SWI/SNF 突变导致癌症和神经系统疾病的机制、这些突变引起的脆弱性以及针对 SWI/SNF 复合物的努力以及具有治疗效果的合成致死靶点。© 2024。Springer Nature Limited。

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.© 2024. Springer Nature Limited.