Loss and revival of androgen receptor signaling in advanced prostate cancer

Abstract

Targeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence.

Fig. 1. Control of AR expression during PCa progression.

a The de-differentiation/lineage plasticity of androgen receptor (AR)-positive to AR-negative disease is likely dependent on the extent of AR inhibition (duration and/or type of inhibitors) and the existence of genetic and epigenetic adaption mechanisms (e.g., SOX2, TP53, RB1, N-MYC, EZH2), while resistance to androgen deprivation therapy (ADT) alone typically involves adaptation mechanisms in the AR pathway. b Prostate cancer growth and survival are dependent on testosterone (T). Testosterone converts locally to dihydrotestosterone (DHT), which binds and activates the AR and causes translocation to the nucleus. Here, AR promotes the transcription of cell cycle genes that promote cancer cell proliferation. ADT initially leads to the regression of the tumor but cancer cells often become resistant, referred to as castration-resistant prostate cancer (CRPC). At this stage, cancer cells adapt to the lower availability of DHT by acquiring gain of function mutations and amplifications on the AR gene. Upon exposure to ARSi (e.g., enzalutamide, abiraterone), prostate cancer cells may more likely undergo de-differentiation into AR-negative prostate cancer, which is associated with extensive rewiring of transcription and chromatin structure. c Scheme of different signaling pathways that can lead to AR epigenetic silencing and protein loss in prostate cancer cells. AR-independent prostate cancer cells can re-express AR protein through exogenous stimuli (in green) that block AR repression. Once re-activated, AR can re-sensitize those cells to ARSi. Aza azacitidine, NGF nerve growth factor, TSA Trichostatin A.

Fig. 2. Perspective functional approaches related to AR expression in advanced PCa.

a Characterization of cellular, microenvironmental, and molecular changes associated with the transition of AR-positive to AR-negative disease. b Identification of susceptibilities and small molecule compounds that target AR-negative disease, the switch of AR-positive to negative disease, and the reversal of AR-negative to -positive disease.