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-suppressive 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–mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)–dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 05, 2022
- Source ID
- 10.1158/2159-8290.cd-21-1671
Entities
People
- Amish J. Patel
- Charles Rudin
- Cindy J. Lee
- Cristina R Antonescu
- Dan Li
- Deyou Zheng
- Elissa W.P. Wong
- Emily Giff
- Eve Fishinevich
- Gabriella Bayshtok
- Jacob Glass
- Jesper L Maag
- Jonathan A. Fletcher
- Joseph M. Scandura
- Juan Yan
- Melissa B. Pappalardi
- Michael T McCabe
- Miguel A Miranda-Román
- Mohini R. Pachai
- Naitao Wang
- Ping Chi
- Richard Koche
- Rohan Misra
- Sarah Warda
- Sarat Chandarlapaty
- Yinuo Meng
- Yu Chen
Organizations
- Albert Einstein College of Medicine
- Cornell University
- GSK
- Geoffrey Beene Cancer Research Center
- Harvard Medical School
- Memorial Sloan Kettering Cancer Center
- National Institutes of Health
- United States Department of Defense
- Weill Cornell Medicine