Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges

Abstract

Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone and enzalutamide, enable stronger blockade of the androgen receptor (AR) axis and longer survival of men with castration-resistant prostate cancer (CRPC). However, the extent of the improved survival remains insufficient and the majority of patients eventually develop resistance to these novel agents. Some patients develop resistance against ARAT treatment through mechanisms termed "complete AR independence" or "AR indifference", and no longer require activation of the AR axis. However, a considerable proportion of CRPC patients remain persistently dependent on AR or its downstream signaling pathways. Ligand-independent activation of the AR, an AR axis-dependent mechanism, is mediated by truncated forms of ARs that lack the ligand-binding domain (LBD), arising as products of AR splicing variants or nonsense mutations of AR. Post-translational modifications of ARs can also contribute to ligand-independent transactivation of the AR. Other mechanisms for AR axis activation are mediated by pathways that bypass the AR. Recent studies revealed that the glucocorticoid receptor can upregulate a similar transcription program to that of the AR, thus bypassing the AR. ARAT agents are essentially ineffective for CRPC driven by these AR-independent mechanisms. This review article describes recent efforts to overcome these refractory machineries for the development of next-generation AR axis blockade in CRPC.

Keywords: androgen receptor; castration-resistant prostate cancer; drivers; heterogeneity.

Figure 1

Suggested mechanisms of resistance to second-generation androgen receptor axis-targeted (ARAT) agents, classified into three groups by their dependency on the androgen receptor (AR) and its downstream signals: persistent AR transactivation, bypassing AR, and AR indifference. DHT = dihydrotestosterone; NE = neuroendocrine; Pca = prostate cancer.

Figure 2

Multi-dimensional classes for tumor heterogeneity, including four types of diversity: (A) intra-tumoral, (B) inter-tumoral, and (C) metachronous heterogeneity. Tumors with different colors represent different clonalities or biological properties.

Figure 3

Schematic illustration depicting the extent of tumor heterogeneity. As the disease progresses in nature (A) or against therapeutic pressure (B), the extent of tumor heterogeneity is exponentially increased.