EZH2 Inhibitors Sensitize Breast Cancer to HER2 Kinase Inhibitors through Cooperative Effects on YAP and Proapoptotic Regulators

Human epidermal growth factor receptor 2-positive (HER2+) tumors account for 20% of breast cancers. Although a variety of HER2-targeted therapies have been developed, tumors can exhibit de novo or acquired resistance, and metastatic disease remains incurable. In this study, we showed that EZH2 inhibitors shift the epigenetic state of HER2+ tumors, dramatically enhancing baseline responses to HER2 kinase inhibitors and resensitizing drug-resistant tumors in vitro and in vivo. Specifically, EZH2 silenced the proapoptotic gene BMF by catalyzing H3K27 trimethylation (H3K27me3) at regulatory sequences. EZH2 inhibitors promoted the loss of H3K27me3, but this stimulated the binding of repressive YAP/TEAD complexes at the BMF locus, which still restricted expression. However, in the presence of EZH2 inhibitors, HER2 kinase inhibitors triggered the dissociation of repressive YAP/TEAD complexes, potently upregulated BMF, and killed resistant cells. Accordingly, EZH2 inhibitors cooperated with genetic or pharmacologic inhibition of YAP/TEAD, which similarly induced BMF expression and apoptosis. Together, these findings show how EZH2 and YAP/TEAD coordinately insulate the BMF locus and demonstrate that EZH2 inhibitors can be used to reprogram HER2+ tumors, resulting in a dramatic sensitization to HER2 kinase inhibitors and enhanced killing of residual disease. SIGNIFICANCE: The combination of EZH2 inhibitors and HER2 kinase inhibitors potently induces tumor regression in HER2+ tumors through effects on YAP and proapoptotic proteins, providing a promising therapeutic strategy for breast cancer.