Abstract 2109: The bromodomain-containing protein ATAD2 promotes GR-mediated enzalutamide resistance in castration-resistant prostate cancer

Abstract

The purpose of this study is to investigate how the activity of the glucocorticoid receptor (GR) is orchestrated to drive the development of enzalutamide resistance in metastatic, castration resistant prostate cancer (mCRPC). Enzalutamide (Enz) is the second-generation antagonist of the androgen receptor, the fuel for the development and progression of prostate cancer. Even though enzalutamide is an effective and well-tolerated treatment in a broad spectrum of patients with castration-resistant prostate cancer, almost all the patients become resistant to the drug eventually. One of the plausible mechanisms to account for the development of enzalutamide resistance is the activation of GR signaling. Upon Enz treatment, GR is upregulated, binds to the cis-regulatory elements of some AR target genes, activates the transcription of these downstream genes and thus circumvents the inhibitory effect of the AR antagonist on prostate cancer cell growth. Unfortunately, it is still unknown how GR-mediated enzalutamide resistance is controlled. Recently, a group of epigenetic regulators, bromodomain (BRD)-containing proteins, have been indicated to promote prostate cancer progression. They function as AR cofactors and dictate the transcriptional activity of the nuclear receptor in response to different ligands. Our prior work found that one of the BRD family members, called ATAD2, plays an essential role in orchestration of GR signaling in the presence of enzalutamide. ATAD2 is significantly elevated upon GR activation and positively regulates GR expression in return. Coimmunoprecipitation demonstrated that ATAD2 binds to GR in enzalutamide-resistant CRPC cells, and it is required for the GR-dependent transcriptional reprogramming in the presence of Enz. Most importantly, we demonstrated that CRPC cells that are Enz-refractory due to the activation of GR signaling become Enz sensitive when ATAD2 is depleted All these findings suggest that ATAD2 acts as a cofactor for GR to induce a gene expression pattern that results in Enz-refractory phenotype in CRPC cells. Our work will not only provide an in-depth insight into the mechanisms underlying enzalutamide resistance, but also lay the foundation for the development of novel therapeutic strategies targeting glucocorticoid receptor (GR) signaling to treat this lethal disease. Citation Format: Richard De La Rosa. The bromodomain-containing protein ATAD2 promotes GR-mediated enzalutamide resistance in castration-resistant prostate cancer [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 2109.