Abstract 116: Targeting EZH2 catalytic independent functions in breast cancer

Abstract

Abstract Advances in drug discovery have enabled the development of catalytic inhibitors or inhibitors that disrupt protein-protein interactions. One validated drug target is the polycomb repressive complex 2 (PRC2), which promotes cancer development and reduces patient survival in multiple cancers. The core of PRC2 consists of Enhancer of Zeste Homolog 2 (EZH2) and Embryonic Ectoderm Development (EED). Currently, inhibitors targeting the catalytic site of EZH2 were efficacious in inhibiting a subset of blood cancers. In addition, a recently developed peptidomimetic inhibitor that disrupts the EED-EZH2 interaction also inhibits PRC2 activity and decreases proliferation of solid tumors. In this study, we investigated the effects of EZH2 protein depletion versus EZH2 catalytic inhibition with two small molecule inhibitors, GSK126 (an EZH2 catalytic inhibitor) and DZNep (a histone methylation inhibitor that depletes EZH2). We found that catalytic inhibition of EZH2 was insufficient to block cancer cell proliferation whereas depletion of EZH2 was effective at killing cancer cells. This study suggests that depleting EZH2 to inhibit both catalytic dependent and independent functions could be useful in the treatment of solid tumors such as breast cancer. Citation Format: Keng Gat Lim. Targeting EZH2 catalytic independent functions in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 116. doi:10.1158/1538-7445.AM2015-116