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

Abstract

Medical or surgical castration serve 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 HSP90 and FKBP52), pioneer factors (including 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, and to continuing to improve treatments for prostate cancer and for overcoming castration-resistance.

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

“…Several such co-regulators have emerged as potential novel pharmaceutical targets, due to their ability to regulate the function of their relevant nuclear receptor, including the androgen receptor [47]. Among them, the family of Steroid/Nuclear receptor coactivator (SRC or NCOA) and especially its first member (NCOA1 or SRC-1) has been reported to mediate estrogen-related CXCL12 enhanced transcription in MCF-7 cells [48], while the role of ΝCΟΑ2 in breast cancer is less well characterized.…”

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

“…Androgen plays pivotal roles in the progression of prostate cancer (PCa) (1), the second most commonly diagnosed cancer among man worldwide (2). Accordingly, androgen deprivation therapy (ADT), which blocks androgen production or action through either physical castration or chemical castration, is the first line treatment for locally advanced or metastatic PCa (3-5).…”

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…Moreover, aberrant upregulation of the SRCs is even more pronounced in CRPC (Taylor et al 2010, Grasso et al 2012, Cancer Genome Atlas Research 2015, Robinson et al 2015, Kumar et al 2016. Mechanistically, increased SRC expression enhances AR signaling in low androgen settings and also potentiates alternative ligand usage (Agoulnik & Weigel 2009, Foley & Mitsiades 2016. The clinical relevance of these factors is perhaps best emphasized by the finding that constitutive overexpression of SRC-2 in the mouse prostate epithelium was sufficient for the development of prostate adenocarcinoma in mice, whereas SRC-2 depletion prevented CRPC development in PTEN-deficient mice (Qin et al 2014).…”

“…Recent reviews have described in detail the current state-of-play in terms of targeting key members of the AR interactome (Biron & Bedard 2015, Foley & Mitsiades 2016, including chaperones (HSP90, HSP27 and others), pioneer factors (e.g. FOXA1 and GATA2) and transcriptional coactivators.…”