Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor

Abstract

Rhabdoid tumor (RT) is a pediatric cancer characterized by the inac-tivation of SMARCB1, a subunit of the SWI/SNF chromatin remodel-ing 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. Mithra-mycin 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, recapitu-lated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice.