8. Naiara Perurena, PhD

The receptor tyrosine kinase HER2 is overexpressed and/or amplified in around 20% of breast cancers and functions as an oncogenic driver. While HER2 inhibitors have dramatically improved the clinical outcome of HER2+ breast cancer, tumors can exhibit de novo or acquired resistance and metastatic disease remains incurable. Therefore, we sought to identify additional co-targets that when inhibited, potentiate the effects of HER2 inhibitors and overcome/delay resistance. EZH2 is an epigenetic regulator that represses transcription by depositing trimethyl marks at H3K27. EZH2 is overexpressed in 84% of HER2+ breast cancers and has been shown to contribute to breast cancer development and metastasis. Here we show that EZH2 inhibitors shift the epigenetic state of HER2+ tumors, enhancing baseline responses to HER2 kinase inhibitors and re-sensitizing drug resistant tumors in vitro and in vivo. Specifically, we report that EZH2 normally silences the pro-apoptotic gene BMF. Accordingly, EZH2 inhibitors remove these repressive marks; however, this stimulates the binding of repressive YAP/TEAD complexes, restraining BMF expression. Once tumors are exposed to EZH2 inhibitors, genetic or chemical inhibition of YAP/TEAD rapidly induces BMF expression and apoptosis. Similarly, in the presence of EZH2 inhibitors, HER2 kinase inhibitors trigger the dissociation of YAP/TEAD complexes from the chromatin, upregulate BMF, and kill resistant cells. Together these studies show that EZH2 and YAP 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.