Purpose: Rhabdoid tumor is a pediatric cancer characterized by the biallelic inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. SMARCB1 inactivation leads to SWI/SNF redistribution to favor a proliferative dedifferentiated cellular state. Although this deletion is the known oncogenic driver, SWI/SNF therapeutic targeting remains a challenge. Experimental Design: We define a novel epigenetic mechanism for mithramycin using biochemical fractionation, chromatin immunoprecipitation sequencing (ChIP-seq), and a dual spike-in assay for transposase accessible chromatin sequencing (ATAC-seq). We correlate epigenetic reprogramming with changes with chromatin A/B compartments and promoter accessibility with chromHMM models and RNA-seq. Finally, we demonstrate durable, marked tumor response in an intramuscular rhabdoid tumor xenograft model. Results: Here we show mithramycin and a second-generation analogue EC8042 evict mutated SWI/SNF from chromatin and are effective in rhabdoid tumor. SWI/SNF blockade triggers chromatin compartment remodeling and promoter reprogramming leading to differentiation and amplification of H3K27me3, the catalytic mark of PRC2. Treatment of rhabdoid rumor xenografts with EC8042 leads to marked, durable tumor regression and differentiation of the tumor tissue into benign mesenchymal tissue, including de novo bone formation. Conclusion: Overall, this study identifies a novel therapeutic candidate for rhabdoid tumor and an approach that may be applicable to the 20% of cancers characterized by mutated SWI/SNF.

Direct therapeutic targeting of SWI/SNF induces epigenetic reprogramming and durable tumor regression in rhabdoid tumor