Moving Beyond the Androgen Receptor (AR): Targeting AR-Interacting Proteins to Treat Prostate Cancer

Abstract

Medical or surgical castration serves as the backbone of systemic therapy for advanced and metastatic prostate cancer, taking advantage of the importance of androgen signaling in this disease. Unfortunately, resistance to castration emerges almost universally. Despite the development and approval of new and more potent androgen synthesis inhibitors and androgen receptor (AR) antagonists, prostate cancers continue to develop resistance to these therapeutics, while often maintaining their dependence on the AR signaling axis. This highlights the need for innovative therapeutic approaches that aim to continue disrupting AR downstream signaling but are orthogonal to directly targeting the AR itself. In this review, we discuss the preclinical research that has been done, as well as clinical trials for prostate cancer, on inhibiting several important families of AR-interacting proteins, including chaperones (such as heat shock protein 90 (HSP90) and FKBP52), pioneer factors (including forkhead box protein A1 (FOXA1) and GATA-2), and AR transcriptional coregulators such as the p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2, SRC-3, as well as lysine deacetylases (KDACs) and lysine acetyltransferases (KATs). Researching the effect of-and developing new therapeutic agents that target-the AR signaling axis is critical to advancing our understanding of prostate cancer biology, to continue to improve treatments for prostate cancer and for overcoming castration resistance.

Fig. 1

Comparison of the full-length AR and two AR variants. The full-length AR is comprised of eight exons (a) which make up the amino-terminal domain (NTD), the DNA-binding domain (DBD), a hinge region, and the carboxy-terminal ligand-binding domain (LBD). The ARv7—also known as AR3—contains exons 1–3 (b), comprising the NTD and the DBD, followed by a short cryptic exon encoding 16 amino acids which are not present in the full-length AR. The LBD is missing in the ARv7, resulting in a constitutively active variant. The ARv567es (c) contains exons 1–4 but is missing exons 5–7. In addition, exon 8 has a translational frameshift

Fig. 2

Representative cartoon of the canonical AR signaling axis in a normal prostate epithelial cell. Androgens diffuse through the plasma membrane into the cytosol, where they bind to the chaperone-sequestered AR and induce a conformational change, resulting in its nuclear translocation and dimerization. In the nucleus, pioneer factors such as GATA-2 and FoxA1 make the chromatin more accessible to other transcription factors and allow dimerized AR to bind to its hormone response elements on chromatin. Once bound, AR recruits coregulator proteins that help assemble the transcriptional machinery and result in the transcription of the AR-target genes

Fig. 3

Representative cartoon of currently FDA-approved prostate cancer therapies, their mechanisms of action, and proposed mechanisms of resistance. Therapies include GnRH analogs that suppress gonadal androgen synthesis, small molecule androgen synthesis inhibitors (e.g., abiraterone) that can block enzymatic steps required for androgen steroidogenesis, androgen receptor antagonists (e.g., enzalutamide) that bind to the AR LBD and prevent activation, and microtubule inhibitors that can disrupt the cell cycle and also may prevent AR translocation into the nucleus. Mechanisms of resistance include intratumoral androgen production to locally generate ligand for the AR, overexpression of AR (frequently through amplification of the AR gene) to enhance sensitivity to low levels of ligand, AR LBD mutations to relax stringency for the activating ligand, ARVs which are constitutively active, and other nuclear receptors substituting for the AR

Fig. 4

a Chaperone (e.g., Hsp90) inhibitors can disrupt AR protein stabilization or proper folding and result in degradation and/or dysfunction of the AR protein. b Pioneer factor (e.g., FoxA1, GATA2) inhibitors may prevent the AR from accessing response elements on chromatin or may interfere with the ability of AR to recruit coregulators needed for transcriptional activity. c p160 steroid receptor coactivator (SRC) inhibitors may prevent the recruitment of the transcriptional machinery components required for efficient transcription. d KAT and KDAC inhibitors may directly modulate post-translational modifications on the AR itself, reducing its activity or may interfere with chromatin remodeling to make the chromatin less amenable for active transcription