Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications

Abstract

Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient's response to androgen ablation therapy is variable, and 20-30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.

Keywords: AR antagonists; AR resistance; AR variants; AR-V7; androgen receptor; prostate cancer.

Figure 1

Transcript structures for full-length androgen receptor (AR) and the splice variant AR-V7. Peptide positions are marked according to GRCh36/hg18 human genome sequences (not drawn to scale). Reproduced, with permission, from Luo J. Development of AR-V7 as a Putative Treatment Selection Marker for Metastatic Castration-Resistant Prostate Cancer. Asian J. Androl. 2016, 18, 580–585; Licensed under a Creative Commons Attribution 4.0 Unported License (Available at https://creativecommons.org/licenses/by/4.0/). Abbreviations: AR-FL, full-length androgen receptor; DBD, DNA-binding domain; LBD, ligand-binding domain; mRNA, messenger RNA; NTD, N-terminal domain; UTR, untranslated region.