We herein identify a pharmacogenetic interaction between EZH2 as a whole (independent of its enzymatic activity) and oncogenic MYC(N), predicting that the enzymatic inhibitors now in clinical development may be ineffective in MYC(N)-driven cancers unless they are capable of depleting EZH2 and MYC(N) or disrupting EZH2-MYC(N) interaction. Here, MYC is linked to cancer.