Targeting Histone Modification Crosstalk as a Therapeutic Strategy for EZH2-aberrant Solid Tumors

Mutations or aberrant upregulation of the histone methyltransferase EZH2 occur frequently in human cancers yet EZH2-targeted therapies have only shown very limited clinical benefits in hematological malignancies. We report here that upon EZH2 inhibition, MLL1 interacts with p300/CBP complex that directs H3K27me loss to gain of H3K27ac modification. This histone modification crosstalk leads to transcriptional reprogramming that restricts the therapeutic response to EZH2 inhibition. Concurrent inhibition of H3K27 methylation and acetylation results in transcriptional repression and growth dependency on the MAPK signaling pathway in a large cancer subset. In pre-clinical models encompassing a broad spectrum of EZH2-aberrant solid tumors