Mechanisms of androgen receptor activation in castration-resistant prostate cancer

Abstract

Systemic treatment of advanced prostate cancer is initiated with androgen deprivation therapy by gonadal testosterone depletion. Response durations are variable and tumors nearly always become resistant as castration-resistant prostate cancer (CRPC), which is driven, at least in part, by a continued dependence on the androgen receptor (AR). The proposed mechanisms that underlie AR function in this clinical setting are quite varied. These include intratumoral synthesis of androgens from inactive precursors, increased AR expression, AR activation through tyrosine kinase-dependent signaling, alterations in steroid receptor coactivators, and expression of a truncated AR with constitutive activity. Various pharmacologic interventions have clinically validated some of these mechanisms, such as those that require the AR ligand-binding domain. Clinical studies have failed to validate other mechanisms, and additional mechanisms have yet to be tested in patients with CRPC. Here, we review the mechanisms that elicit AR activity in CRPC, with a particular focus on recent developments.

Figure 1.

Enzymatic reactions and steroid modifications required for DHT synthesis. The structure of cholesterol, with carbons 3, 5, and 17 labeled, is shown in the upper left. Modifications of carbons 3 and 5 on the steroid A and B rings are catalyzed by 3βHSD and SRD5A in the adrenal pathways and pregnanes in the backdoor pathways (not shown). Conversion from 17-ketosteroids to 17β-hydroxysteroids is catalyzed by the 17βHSD isoenzymes. The conventional pathway occurs through conversion from DHEA → androstenedione → testosterone → DHT. The dominant adrenal pathway (5α-dione pathway) occurs through DHEA → androstenedione → 5α-dione → DHT. A missense mutation in 3βHSD1 (shaded box) increases flux through a metabolic step (DHEA → androstenedione) that is otherwise rate-limiting in the synthesis of DHT, permitting the development of CRPC. Mutant 3βHSD1 may also regulate metabolic flux through the backdoor pathways (not shown).