EZH2 Inhibitors Sensitize Breast Cancer to HER2 Kinase Inhibitors through Cooperative Effects on YAP and Pro-apoptotic Regulators

Abstract Human epidermal growth factor receptor 2 positive (HER2+) tumors account for 20% of breast cancers. While a variety of HER2-targeted therapies have been developed, tumors can exhibit de novo or acquired resistance, and metastatic disease remains incurable. Here, we showed that EZH2 inhibitors shift the epigenetic state of HER2+ tumors, dramatically enhancing baseline responses to HER2 kinase inhibitors and re-sensitizing drug-resistant tumors in vitro and in vivo. Specifically, EZH2 silenced the pro-apoptotic 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 pharmacological 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.