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Summary 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. Graphical Abstract Highlights • Epigenetic signature profiling in ∼100 tumor lines with different EZH2i sensitivities • MLL1-p300/CBP-mediated H3K27ac gain and oncogenic reprogramming limit EZH2i response • H3K27ac co-inhibition improves EZH2i efficacy but activates MAPK in some cancers • MLL1 level and inhibiting feedback MAPK activation expand EZH2i utility and precision Epigenetic crosstalk targeting together with MLL1-based stratification and inhibiting feedback MAPK activation expand EZH2 inhibitors’ therapeutic utility and efficacy in patient-derived solid tumor models. [ABSTRACT FROM AUTHOR]