Targeting the Androgen Signaling Axis in Prostate Cancer

Abstract

Activation of the androgen receptor (AR) and AR-driven transcriptional programs is central to the pathophysiology of prostate cancer. Despite successful translational efforts in targeting AR, therapeutic resistance often occurs as a result of molecular alterations in the androgen signaling axis. The efficacy of next-generation AR-directed therapies for castration-resistant prostate cancer has provided crucial clinical validation for the continued dependence on AR signaling and introduced a range of new treatment options for men with both castration-resistant and castration-sensitive disease. Despite this, however, metastatic prostate cancer largely remains an incurable disease, highlighting the need to better understand the diverse mechanisms by which tumors thwart AR-directed therapies, which may inform new therapeutic avenues. In this review, we revisit concepts in AR signaling and current understandings of AR signaling-dependent resistance mechanisms as well as the next frontier of AR targeting in prostate cancer.

FIG 1.

Androgen signaling in prostate cancer is highlighted by multiple receptor and pre/postreceptor mechanisms that serve as targets for different therapeutic approaches. Androgen biosynthesis is tightly regulated by the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, which govern the production of gonadal and adrenal androgens that serve as precursors for DHT, the principal AR ligand in the prostate (pre--receptor activity). On ligand binding, AR translocates from the cytoplasm to the nucleus to bind to DNA as a homodimer, permitting transactivation of target genes and pathways (postreceptor activity). Examples of different clinically approved as well as investigational inhibitors are highlighted. ACTH, adrenocorticotropic hormone; AR, androgen receptor; ARE, androgen response element; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; HSP, heat shock protein; LH, luteinizing hormone; NTD, N-terminal domain; PROTACs, proteolysis-targeting chimeras; PSA, prostate-specific antigen; SARDs, selective androgen receptor degraders.

FIG 2.

A timeline of key translational discoveries and therapeutic innovations in the treatment of PCa. Illustration was created with BioRender. ADT, androgen deprivation therapy; AR, androgen receptor; CRPC, castration-resistant prostate cancer; DHT, dihydrotestosterone; FDA, US Food and Drug Administration; GnRH, gonadotropin-releasing hormone; mCSPC, metastatic castration-sensitive prostate cancer; PCa, prostate cancer; PSA, prostate-specific antigen.

FIG 3.

Several key pathways of steroidogenesis contributing to androgen biosynthesis, which include the canonical pathway of DHT synthesis through testosterone (blue) as described in normal physiology, as well as the 5α-androstanedione (5α-dione) pathway, which is the primary route of DHT biosynthesis from adrenal precursors in prostate cancer.^, More recently, the 11-oxygenated androgen pathway has gained increasing recognition for generation of 11-keto-testosterone and 11-keto-DHT, which can serve as bona fide AR agonists in prostate cancer (green). In addition, multiple other potentially relevant pathways exist, including the alternative, backdoor pathway (orange). Of note, this simplified schematic is not comprehensive in depicting all possible pathways, including those through 17α-OH progesterone derivatives as intermediates. AD, androstenedione; AR, androgen receptor; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; HSD, hydroxysteroid dehydrogenase.

FIG 4.

The AR gene locus and protein. The mRNA transcript encoding the full-length AR protein encompasses eight exons, which consists of four major functional protein domains. AR mutations most frequently occur in the LBD. Several AR-Vs including AR-V7, AR-V9, and AR-V12/ARv567es are depicted as well, including their corresponding exons. AR, androgen receptor; AR-Vs, AR variants; DBD, DNA-binding domain; LBD, ligand-binding domain; NTD, N-terminal domain; UTR, untranslated region.