Persistent androgen receptor addiction in castration-resistant prostate cancer

Abstract

It is now understood that persistent activation of the androgen receptor (AR) signaling pathway often underlies the development of castration-resistant prostate cancer (CRPC). This realization led to renewed interest in targeting the AR and ultimately to the development of the potent next-generation AR-directed agents abiraterone and enzalutamide. While these drugs prolong survival in men with CRPC, they are unfortunately not curative. Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops. In this context, activation of the AR signaling program can occur through a number of molecular adaptations, including alterations leading to persistent canonical AR signaling (e.g., AR amplification/overexpression, elucidations/concentration of intratumoral androgens), activation of the AR program via feedback pathways (e.g., AKT/mTOR/Pi3K, HER2/Neu), and activation of the AR program via mutation or substitution (e.g., AR ligand binding domain mutation; AR splice variants; glucocorticoid receptor signaling). This review will provide an overview of the more clinical relevant (i.e., druggable) pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms.

Figures

Fig. 1

Androgen Receptor Structure. a. The AR gene is located on the X chromosome at position Xq11-Xq12. It is composed of eight exons, which encode for four regions: N-terminal domain (NTD), DNA binding domain (DBD), the hinge region and the ligand binding domain (LBD). b. Several cryptic exons (CE) as well as exon 9 are involved in the formation of several AR splice variants (AR-Vs) which lack the AR ligand binding domain. Four of these AR-Vs have been shown to possess constitutive activity (i.e., AR-V3, AR-V4, AR-V7, and AR-V12)

Fig. 2

Steroidogenesis pathway. Enzymes shown to be upregulated in a castration-resistant state are highlighted red. M mineralocorticoid biosynthesis pathway, G glucocorticoid biosynthesis pathway, A androgen biosynthesis pathway

Fig. 3

Androgen receptor activation pathways. AR transcription can occur either through canonical AR-FL signaling or through cross-talk between alternative signaling pathways. Ligand-independent AR transcription likely occurs through a number of mechanisms and may involve the formation of AR homodimers (as is the case with the AR-FL canonical signaling pathway) or heterodimerization between AR-FL, AR-Vs, and AR-mutants. Cross-talk between signaling pathways likely augment AR transcriptional activity in several ways, including through N-terminal phosphorylation, or by promoting AR nuclear translocation. Key nodes affected by several pathways are highlighted in red. RTK receptor tyrosine kinases, T testosterone, HSP heat-shock proteins, IL6-R IL-6 receptor, CoReg co-regulators