Abstract P1-18-27: Developing a novel combination therapy using EZH2i for HER2+ breast cancer

Abstract

Abstract The receptor tyrosine kinase (RTK) human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-25% of breast cancers and acts as a driver of tumor growth. Though there are FDA-approved agents in the clinic that specifically target HER2, metastatic HER2+ breast cancer remains incurable with a median overall survival of 56.5 months. In addition, the response rates of patients with metastatic disease vary considerably, with 20-50% and 60-80% of patients unresponsive to first- and second-line therapies respectively. Therefore, it is necessary to discover a new therapy able to overcome the therapeutic resistance of HER2+ breast cancer that currently leads to patient relapse, and ultimately, death. One approach that our lab has successfully used to develop more effective therapies for other tumor types is to co-target different oncogenic pathways for a more potent effect. A target of interest is the histone methyltransferase enhancer of zeste homolog 2 (EZH2), which is overexpressed in many cancer types including breast, prostate, bladder, gastric, lung, and hepatocellular carcinoma. Interestingly, in breast cancer, EZH2 is overexpressed in the more aggressive subtypes including HER2+. EZH2 expression levels correlate with a worse prognosis and parallels cancer progression. We chose to investigate the therapeutic potential of combining EZH2 inhibitors (EZH2i) with lapatinib, an FDA-approved HER2-targeted therapy for late stage HER2+ breast cancer. In vitro assays show that the combination has a potent cytotoxic effect and renders lapatinib-sensitive HER2+ breast lines more sensitive, and causes lapatinib-resistant lines to become sensitive. In addition, in vivo testing of both lapatinib-sensitive and resistant HER2+ xenografts showed potent regression with the combination, confirming the extremely promising results. Using RNA-Seq and ChIP-Seq, we have identified that the Rb/E2F pathway may be involved in the combination’s mechanism of action. We will identify the biological settings in which this combination may be most effective and elucidate its molecular mechanism of action. This work will not only validate a promising new therapeutic combination, but will also provide insight into additional vulnerabilities of HER2+ breast cancer, possibly leading to additional therapeutic strategies. Citation Format: Marina Watanabe, Rysn Kuzmickas, Karen Cichowski. Developing a novel combination therapy using EZH2i for HER2+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-27.