Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis

Abstract

The metabolic functions of androgen receptor (AR) in normal prostate are circumvented in prostate cancer (PCa) to drive tumor growth, and the AR also can acquire new growth-promoting functions during PCa development and progression through genetic and epigenetic mechanisms. Androgen deprivation therapy (ADT, surgical or medical castration) is the standard treatment for metastatic PCa, but patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC). Early studies from many groups had shown that AR was highly expressed and transcriptionally active in CRPC, and indicated that steroids from the adrenal glands were contributing to this AR activity. More recent studies showed that CRPC cells had increased expression of enzymes mediating androgen synthesis from adrenal steroids, and could synthesize androgens de novo from cholesterol. Phase III clinical trials showing a survival advantage in CRPC for treatment with abiraterone (inhibitor of the enzyme CYP17A1 required for androgen synthesis that markedly reduces androgens and precursor steroids) and for enzalutamide (new AR antagonist) have now confirmed that AR activity driven by residual androgens makes a major contribution to CRPC, and led to the recent Food and Drug Administration approval of both agents. Unfortunately, patients treated with these agents for advanced CRPC generally relapse within a year and AR appears to be active in the relapsed tumors, but the molecular mechanisms mediating intrinsic or acquired resistance to these AR-targeted therapies remain to be defined. This review outlines AR functions that contribute to PCa development and progression, the roles of intratumoral androgen synthesis and AR structural alterations in driving AR activity in CRPC, mechanisms of action for abiraterone and enzalutamide, and possible mechanisms of resistance to these agents.

Figure 1

AR structure and responses to binding agonist and antagonist ligands. Androgen binding mediates a conformational change in the position of helix 12 in the LBD. Binding to an FQNLF peptide in the NTD mediates an initial intramolecular N–C interaction, and a subsequent intermolecular interaction may contribute to nuclear localization. AR then binds to androgen-responsive elements at sites that are generally bound initially by the FOXA1 transcription factor, which has been termed a ‘pioneer transcription factor,’ as it opens chromatin locally so AR can access the ARE. These sites also are generally marked by H3K4me2 containing nucleosomes. AR binding displaces a weakly associated central nucleosome, and initiates the assembly of multiple coactivator and chromatin-modifying proteins that loop to the promoter to initiate transcription. LSD1 functions as a critical coactivator for androgen-stimulated genes that is associated with H3K9me2 demethylation, and corepressor for androgen-repressed genes that is associated with H3K4me2 demethylation, but the precise LSD1 mechanisms of action on androgen-stimulated versus -repressed genes remain to be established. The bicalutamide-liganded AR associates more transiently with chromatin, does not effectively mediate coactivator recruitment, and has increased corepressor recruitment. The MDV3100 (enzalutamide) liganded AR localizes in both the nucleus and cytoplasm, but does not detectably associate with chromatin, which may reflect further displacement of helix 12 and abrogation of the N–C interaction.

Figure 2

Increased expression of androgen-repressed genes may contribute to PCa progression after ADT. In the presence of testicular androgen, AR stimulates PCa growth through its positive effects on metabolic genes while its repression of genes mediating DNA synthesis/cell cycle progression is circumvented by activated oncogenic pathways. The initial response to ADT reflects downregulation of metabolic pathways mediating lipid and protein synthesis, but an undesirable effect is to relieve repression of the AR gene, and of genes regulating androgen synthesis and DNA synthesis/cell cycle progression. In CRPC, mechanisms including increased intratumoral androgen synthesis partially restore AR activity and its metabolic functions, but this AR activity is not adequate to decrease expression of the androgen-repressed genes controlling functions that include DNA synthesis/cell cycle progression.

Figure 3

SOX9 is downstream effector of ERG and AR in TMPRSS2:ERG fusion-positive PCa. SOX9 expression can be stimulated by extracellular signals including FGFs and HGF (mediated by their receptors and downstream ERK), and by WNTs though the canonical WNT/β-catenin pathway. AR in fusion-negative cells binds weakly to a site 5′ of the SOX9 gene (S1 site) and can weakly repress basal SOX9 expression (possibly by displacing positive transcription factors). In fusion-positive cells, ERG binds to a cryptic ARE 3′ of the SOX9 gene, with subsequent binding of FOXA1 and strong androgen-stimulated SOX9 expression.

Figure 4

Increased intratumoral androgen synthesis in CRPC and potential mechanisms of resistance to CYP17A1 inhibitors.