Cancer Res

Inactivation of the SWI/SNF complex is a hallmark of multiple human cancers. Here, we showed that SMARCB1 deficient cells, including highly aggressive pediatric malignant rhabdoid tumors (MRTs), display aberrant H3K27ac and H3K27me3 dynamics that confer marked sensitivity to the KDM6A/B inhibitor GSK-J4. This vulnerability was absent in cancers harboring mutations in most other SWI/SNF components; sensitivity was associated with elevated basal autophagy and heightened susceptibility to endoplasmic reticulum stress and the integrated stress response triggered by GSK-J4. Restoration of SMARCB1 expression induced senescence, decreased autophagic flux, and abrogated GSK-J4 sensitivity, while also promoting vascular remodeling required for tumor adaptation under stress. In patient derived orthotopic xenograft models from MRT patients, GSK-J4 treatment robustly suppressed tumor growth. These findings identify a specific dependency of SMARCB1-mutant cancers on H3K27 demethylase activity and underscore the therapeutic potential of targeting this pathway in SWI/SNF deficient tumors.