Remarkable Synergy When Combining EZH2 Inhibitors with YM155 Is H3K27me3-Independent

Simple Summary Systems biology analysis of gene expression across solid tumors identifies a 27 signature that centers on EZH2, the key component of polycomb repressive complex 2. Our study demonstrates that targeting the 27 gene network by the combination of BIRC5 and EZH2 inhibitors achieves remarkable anticancer synergy that is independent of the histone methyltransferase activity of EZH2.Globlal gene expression analysis in combination with pathway analysis shows that combination of YM155, the BIRC5 inhibitor, with EZH2 inhibitors induces unfolded protein response. Targeting multiple molecules in the same biological network may maximize therapeutic efficacy. In this study, we identified a 27-gene module that is highly expressed in solid tumors, encoding actionable targets including EZH2 and BIRC5. The combination of EZH2 inhibitors and a BIRC5 inhibitor, YM155, results in a remarkable synergistic effect. The action of EZH2 inhibitors in this process is independent of the histone methyltransferase activity of polycomb repressive complex 2. Our study reveals a potential therapeutic approach for treating solid tumors by simultaneously targeting EZH2 and BIRC5.