PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry

Abstract

Polycomb Repressive Complex 2 (PRC2) has oncogenic and tumor suppressor roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2 inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2-inactivation increases sensitivity to genetic or small molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor (DNMTi) mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through PKR-dependent double stranded-RNA (dsRNA) sensor. Collectively, our observations posit DNA methylation as a safeguard against anti-tumorigenic cell fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1 targeted therapy.

Select EZH2 inhibitors enhance the viral mimicry effects of DNMT inhibition through a mechanism involving calcium-calcineurin-NFAT signaling

“…Consistent with these findings, perturbing DNA methylation, genetically or as a consequence of chemotherapy/metabolic perturbation, renders cancer cells sensitive to EZH2 inhibition. Conversely, tumors with genetically compromised PRC2 activity are hypersensitive to DNMT inhibition (53,55,125,126). Our studies build from these reports, corroborating the combination anti-proliferative effects of DNMT and EZH2 inhibition in colorectal cancer models while also providing in-depth analysis of the molecular effects of combined DNMT and EZH2 inhibition on the epigenome and transcriptome, the importance of which is discussed below.…”

Distinct genomic landscapes in radiation‐associated angiosarcoma compared with other radiation‐associated sarcoma histologies

“…For instance, both primary and RT‐AS are treated with taxane‐based chemotherapeutic regimens [38]. Further, investigations on the use of small molecular inhibitors of DNA methyltransferase (DNMT1) in sporadic/NF1‐related and RT‐MPNSTs harboring polycomb repressive complex (PRC)‐inactivating mutations are ongoing [39]. Thus, potential molecular targets for precision medicine may be histotype‐dependent.…”

Targeting polycomb repressor complex 2‐mediated bivalent promoter epigenetic silencing of secreted frizzled‐related protein 1 inhibits cholangiocarcinoma progression

“…Numerous ChIP‐Seqs illustrated that detectable PRC2 binding was observed in a relatively small fraction of the genome, overlapping mainly with H3K27me3‐positive CpG islands 41 . It suggests that PRC2 and DNA methylation together protect tumour cells in cancer 42 . Indeed, EZH2 is required for DNA methylation in the promoters of certain genes as a platform to recruit DNA methyltransferases 43 .…”