Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor. Issue 2 (17th December 2020) - Chasse, Maggie H
Abstract: Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. Here we use unbiased screening of cell line panels to identify a heightened sensitivity of rhabdoid tumor to mithramycin and the second‐generation analogue EC8042. The sensitivity of MMA and EC8042 was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion. Mithramycin blocks SMARCB1‐deficient SWI/SNF activity and displaces the complex from chromatin to cause an increase in H3K27me3. This triggers chromatin remodeling and enrichment of H3K27ac at chromHMM‐defined promoters to restore cellular differentiation. These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes. Importantly, a single 3‐day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice. Synopsis: EC8042 is identified as an inhibitor of oncogenic SWI/SNF and a promising therapeutic candidate for rhabdoid tumor. The mechanism of target inhibition is elucidated and used to optimize compound administration, characterize an associated biomarker, and cure mice bearing rhabdoid tumor xenografts. Mithramycin displaced SMARCB1‐deficient SWI/SNF from chromatin. Mithramycin induced epigenetic reprogramming favoring promoters and SWI/SNF bound CTCF sites to induce mesenchymal differentiation. EC8042, a second‐generation mithramycin analogue, induced mesenchymal differentiation to cure three of eight mice bearing rhabdoid tumor xenografts with a single 3‐day infusion of the drug. Abstract : EC8042 is identified as an inhibitor of oncogenic SWI/SNF and a promising therapeutic candidate for rhabdoid tumor. The mechanism of target inhibition is elucidated and used to optimize compound administration, characterize an associated biomarker, and cure mice bearing rhabdoid tumor xenografts.