Abstract 2126: Therapeutic potential of CPI-0209
Authors: Wu Rentian , Zhao Feng , Keller Patricia J. , Mertz Jennifer A. , McGrath John P. , Bryant Barbara , Conery Andrew R. , Sun Kaiming , Wang Jing , Trojer Patrick 
Published: July 2021

Abstract
Second-generation EZH2 inhibitor CPI-0209 has therapeutic potential for androgen receptor-dependent prostate cancer
Rentian Wu, Feng Zhao, Patricia J. Keller, Jennifer A. Mertz, John P. McGrath, Barbara Bryant, Andrew R. Conery, Kaiming Sun, Jing Wang, and Patrick Trojer
Post-translational modification of histones plays critical roles in epigenetic regulation of gene expression. Enhancer of Zeste Homolog 2 (EZH2), a subunit of Polycomb Repressive Complex 2 (PRC2), catalyzes trimethylation of histone H3 on lysine 27 (H3K27me3). Chromatin methylation by EHZ2 promotes chromatin architectural changes and silencing of gene expression. EZH2-mediated gene silencing was shown to contribute to tumor initiation and progression. Amplification and overexpression of EZH2 along with down regulation of its target genes correlate with treatment resistance and poor prognosis in various tumor types including metastatic castration resistant prostate cancer (mCRPC). While most mCRPC patients are initially responsive to agents targeting the androgen receptor (AR) signaling pathway, tumors eventually develop resistance and progress. Other than EZH2 overexpression, mechanisms of resistance involve AR alterations, including AR amplification, alteration of AR splice variants which constitutively activate ARS, and AR mutations that affect native ligand-binding specificity.
CPI-0209 is an orally bioavailable and selective EZH2 and EZH1 inhibitor with highly enhanced potency and extended residence time compared to first-generation EZH2 inhibitors. CPI-0209 is currently being clinically developed as monotherapy and in combination with other cancer therapeutic agents [NCT04104776]. Here we demonstrated that AR-dependent prostate cancer cell lines including LNCaP, 22Rv1 and VCaP were sensitive to CPI-0209 treatment, while AR-independent cell lines like PC3 and DU145 were insensitive to CPI-0209. Sensitivity to CPI-0209 were also observed in AR-dependent cell line-derived xenografts (CDX) and patient-derived xenografts (PDX) models. In AR-dependent cells, CPI-0209 synergized with enzalutamide and overcame the anti-androgens resistance induced by AR alterations. In prostate cancer CDX and PDX models, the combination treatment of CPI-0209 and enzalutamide showed greater tumor growth inhibition compared to enzalutamide monotherapy. Transcriptomic analysis revealed that CPI-0209 treatment modulated both AR-related and AR-independent pathways, which reveals a potential mechanism to explain the synergy of CPI-0209 and AR inhibitors. Thus, our results indicate that CPI-0209 may have the potential to be effective for AR-dependent mCRPC that are resistant to current AR inhibitors, supporting potential clinical development in mCRPC.
Keywords: EZH2, prostate cancer, epigenetics, resistant
Citation Format: Rentian Wu, Feng Zhao, Patricia J. Keller, Jennifer A. Mertz, John P. McGrath, Barbara Bryant, Andrew R. Conery, Kaiming Sun, Jing Wang, Patrick Trojer. Therapeutic potential of CPI-0209 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2126.