Combined inhibition of BETs and HDACs as a potential epigenetics-based therapy for malignant rhabdoid tumor

Malignant rhabdoid tumors (MRT) are highly aggressive pediatric malignancies driven by SMARCB1 loss and consequent epigenetic dysregulation, with dismal survival rates underscoring the need for novel therapies. Given the central role of chromatin modifiers in MRT pathogenesis, we investigated a novel combinatorial epigenetic approach simultaneously targeting histone deacetylases (HDACs) and bromodomain and extraterminal (BET) family proteins. Using a focused epigenetic compound screen across multiple MRT cell lines, we identified that the HDAC inhibitor panobinostat (LBH589) and the BET inhibitor birabresib (OTX015) act synergistically to inhibit cell proliferation, with combination index (CI) values consistently <1. Transcriptomic profiling revealed that this synergy is underpinned by a profound downregulation of cell cycle genes, leading to G1/S phase arrest. Mechanistically, the combination therapy cooperatively restores the expression of the cyclin-dependent kinase inhibitors p21 and p16. This restoration inhibits cyclin D1-CDK4/6 kinase activity, reduces retinoblastoma protein (Rb) phosphorylation, and consequently represses the E2F1 transcriptional program and its key targets, including cyclin A2 and cyclin B1. In vivo, this dual-epigenetic targeting significantly attenuated tumor growth in MRT xenograft models, outperforming either monotherapy, and was associated with suppressed proliferation and E2F1 signaling. Our findings unveil a novel synergistic strategy that pharmacologically recapitulates a core SMARCB1-mediated tumor-suppressive circuit, nominating combined HDAC and BET inhibition as a promising therapeutic avenue for MRT.