Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer

Abstract

Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023

“…Different interactions between AR monomers allow homodimer formation, including interactions between the DBD, the LBD, and N/C interactions (intraand intermolecular). Interrupting these interactions impedes AR signaling and results in a female phenotype in male mice (Askew, Minges, Hnat, & Wilson, 2012;Chauhan & Heemers, 2021;El Kharraz et al, 2021;Nadal et al, 2017;Shaffer, Jivan, Dollins, Claessens, & Gewirth, 2004;van Royen, van Cappellen, de Vos, Houtsmuller, & Trapman, 2012). While DBD and LBD interactions are involved in dimerization, N/C interactions can also occur within the same molecule.…”

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

“…A survey of AR binding and H3K27 acetylation, H3K4 trimethylation and H3K27 trimethylation in 100 primary prostate cancer samples allowed researchers to define three major subgroups [ 120 ]. Comparison between healthy tissue, primary prostate tumor and CRPC shows the AR cistrome to vary significantly [ 84 , 115 , 121 ]. On the other hand, a comparative study of four metastases from one mCRPC patient reveals that most AR-interacting sites on the genome are shared, and they are additionally characterized by strong FOXA1 occupancy and histone H3K27 acetylation [ 122 ].…”