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. Significance: 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

中文翻译：

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癌症中 PRC2 失活突变通过增强病毒拟态增强对 DNMT1 靶向治疗的细胞毒性反应

Polycomb 抑制复合物 2 (PRC2) 在癌症中具有致癌和肿瘤抑制作用。在 PRC2 依赖性癌症中靶向该复合物已取得临床成功，但 PRC2 缺失癌症中的治疗需求尚未得到满足。PRC2 失活突变是高级恶性周围神经鞘瘤 (MPNST) 的一个标志性特征，MPNST 是一种侵袭性肉瘤，预后不良，且没有有效的靶向治疗。通过 MPNST 中的 RNAi 筛选，我们发现 PRC2 失活会增加对 DNA 甲基转移酶 1 (DNMT1) 的遗传或小分子抑制的敏感性，从而增强细胞毒性和抗肿瘤反应。从机制上讲，PRC2 失活部分通过蛋白激酶 R (PKR) 依赖性双链 RNA 传感器放大 DNMT 抑制剂介导的逆转录转座子表达、随后的病毒拟态反应和稳健的细胞死亡。总的来说，我们的观察结果表明，DNA 甲基化可以作为 PRC2 缺失癌症中抗肿瘤细胞命运决定的一种保障措施，从而促进癌症发病机制，这可以通过 DNMT1 靶向疗法进行治疗。意义：PRC2 失活会驱动各种癌症的发生，但针对 PRC2 缺失的治疗仍然具有挑战性。在这里，我们发现 PRC2 失活突变为通过 DNMT1 抑制剂进行治疗干预建立了肿瘤环境特异性的责任，这导致通过感知去抑制的逆转录转座子介导的先天免疫信号传导，并伴随着增强的细胞毒性。参见 Guil 和 Esteller 的相关评论，第 17 页。2020 年。本文在本期专题第 12 页中重点介绍。2007年