SMARCB1 Deficiency in Tumors Confers Vulnerability to H3K27 Demethylase Inhibitors via Autophagy Disruption

Inactivation of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is a hallmark of multiple human cancers. In this study, we showed that SMARCB1-deficient cells, including highly aggressive pediatric malignant rhabdoid tumors (MRT), 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 patients with MRT, 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. SIGNIFICANCE: SMARCB1-mutant tumors exhibit aberrant H3K27 regulation and elevated basal autophagy that render them sensitive to inhibition of KDM6A and KDM6B, highlighting a therapeutic strategy for this aggressive malignancy.