Targeting the adaptive molecular landscape of castration-resistant prostate cancer

Abstract

Castration and androgen receptor (AR) pathway inhibitors induce profound and sustained responses in advanced prostate cancer. However, the inevitable recurrence is associated with reactivation of the AR and progression to a more aggressive phenotype termed castration-resistant prostate cancer (CRPC). AR reactivation can occur directly through genomic modification of the AR gene, or indirectly via co-factor and co-chaperone deregulation. This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways. In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways. We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC.

Keywords: androgen receptor; castration‐resistant prostate cancer; stress response; survival pathways; tumour heterogeneity.

Figure 1

Mechanisms of androgen receptor reactivation in castration-resistant prostate cancer The top left panel depicts the activation of the androgen receptor (AR) by its natural ligand (dihydrotestosterone, DHT) in a normal cell. Induction of functional tumour suppressors prevents the AR transcriptional program from driving mitogenesis. The top right panel shows adaptive and genomic changes in CRPC cells that can lead to direct reactivation of the AR in the absence of natural ligand. White boxes illustrate novel agents (targeted against AR reactivation) recently approved or currently undergoing clinical evaluation for the treatment of CRPC. The bottom panel demonstrates the contribution of AR co-factors and co-chaperones to the reactivation of AR in CRPC and illustrates novel targeting strategies in development.

Figure 2

Neuroendocrine transdifferentiation in response to AR axis inhibition Illustration of the adaptive response to AR axis inhibition that can result in prostatic adenocarcinoma transforming to neuroendocrine prostate cancer. Typical disease markers including chromogranin A (CHGA) are shown at either end of the diagram. Genomic aberration thought to facilitate transdifferentiation is indicated above the arrow. Small arrows indicate up- and down-regulation, respectively.

Figure 3

Applicability of the liquid biopsy for CRPC Schematic showing the relative strengths and weaknesses of a tumour tissue biopsy, circulating tumour cell analysis, and cell-free DNA analysis for monitoring patients with CRPC. WGA = whole-genome amplification.