Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.

中文翻译：

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靶向表观遗传串扰作为EZH2异常实体瘤的治疗策略。

EZH2的突变或异常上调在人类癌症中经常发生，但是EZH2抑制剂（EZH2i）的临床益处仍然不能令人满意，并且仅限于某些血液系统恶性肿瘤。我们介绍了对EZH2i具有各种敏感性的一大类癌细胞系中的全球翻译后组蛋白修饰变化。我们在这里报告了由MLL1与p300 / CBP复合物相互作用介导的致癌转录重编程，该基因将H3K27me丢失引导至相互的H3K27ac增益并限制了EZH2i反应。同时抑制H3K27me和H3K27ac会导致癌症亚群中的转录抑制和MAPK途径依赖性。在涵盖广泛的EZH2异常实体瘤，EZH2和BRD4抑制剂组合的临床前模型中，或包含MAPK抑制作用的三联组合显示出强大的疗效和非常可耐受的毒性。我们的结果表明，基于肿瘤内源性MLL1表达以及同时抑制表观遗传串扰和反馈MAPK激活的EZH2异常肿瘤的一种有吸引力的精密治疗策略。