PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry.
Amish J PatelSarah WardaJesper L V MaagRohan MisraMiguel A Miranda-RománMohini R PachaiCindy J LeeDan LiNaitao WangGabriella BayshtokEve FishinevichYinuo MengElissa W P WongJuan YanEmily GiffMelissa B PappalardiMichael T McCabeJonathan A FletcherCharles M RudinSarat ChandarlapatyJoseph M ScanduraRichard P KocheJacob Lowell GlassCristina R AntonescuDeyou ZhengJuliet ChenPing ChiPublished in: Cancer discovery (2022)
PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.