The SWI/SNF complex is a remodeler of chromatin that unspools DNA from the fundamental unit of its histone protein packaging—the nucleosome—to make sequences that initiate and boost gene expression available for recognition by the cellular machinery assigned those tasks. Drugs that target SWI/SNF activity for cancer therapy are now in clinical development, as the complex is mutated in nearly a quarter of all cancers. But relatively little is known about the full spectrum of SWI/SNF gene targets and what the functional effects of its inhibition might be. Ludwig Harvard’s Karen Adelman and colleagues used an inhibitor of SWI/SNF activity to address those questions in experiments conducted using multiple cancer cell lines. They reported in a November paper in Cell that SWI/SNF inhibition can fall short of its intended effect because an alternative chromatin remodeler, EP400, steps up to compensate for its loss. Inhibiting both remodelers resulted in suppression of cancer cell growth in patient-derived cell lines of acute myeloid leukemia, the pediatric brain cancer diffuse intrinsic pontine glioma, prostate cancer and non-small cell lung cancer. Aside from identifying a new “synthetic lethality” and potential drug target for combination therapy, the findings uncover molecular genomic features that could predict sensitivity to SWI/SNF inhibition.
Global identification of SWI/SNF targets reveals compensation by EP400
Cell, 2023 November 2