Undesirable Status of Prostate Cancer Cells after Intensive Inhibition of AR Signaling: Post-AR Era of CRPC Treatment

Abstract

Recent advances in prostate cancer (PC) research unveiled real androgen receptor (AR) functions in castration-resistant PC (CRPC). Moreover, AR still accelerates PC cell proliferation via the activation of several mechanisms (e.g., mutation, variants, and amplifications in CRPC). New-generation AR signaling-targeted agents, inhibiting extremely the activity of AR, were developed based on these incontrovertible mechanisms of AR-induced CRPC progression. However, long-term administration of AR signaling-targeted agents subsequently induces the major problem that AR (complete)-independent CRPC cells present neither AR nor prostate-specific antigen, including neuroendocrine differentiation as a subtype of AR-independent CRPC. Moreover, there are few treatments effective for AR-independent CRPC with solid evidence. This study focuses on the transformation mechanisms of AR-independent from AR-dependent CRPC cells and potential treatment strategy for AR-independent CRPC and discusses them based on a review of basic and clinical literature.

Keywords: androgen receptor; castration-resistant prostate cancer; double-negative castration-resistant prostate cancer; neuroendocrine prostate cancer.

Figure 1

Schematic presentation of the androgen receptor (AR) bypass/crosstalk mechanisms. AR androgen receptor, EGF epidermal growth factor, GR glucocorticoid receptor, IGF-1 insulin-like growth factor-1, IL interleukin, KGF keratinocyte growth factor, PSA prostate-specific antigen, RTK receptor tyrosine kinases. Solid arrows indicate activation and broken arrows indicate interaction.

Figure 2

Neuroendocrine prostate cancer (NEPC) is characterized by loss of tumor suppressors, activation of oncogenic drivers, and epigenetic changes. AR androgen receptor, NE neuroendocrine, TF transcription factor. Up and down arrows indicate upregulation and downregulation, respectively.

Figure 3

Schematic presentation of the representative transition states the underlying lineage plasticity that occurs during CRPC progression following strong suppression of AR signaling. The long-term use of potent ARSTAs and additional molecular modifications were suggested to may be eventually lead to lethal DNPC via the biological changes between AR-dependent CRPC and NEPC. AR androgen receptor, NE neuroendocrine, ARSTAs AR signaling-targeted agents, CRPC castration-resistant prostate cancer, NEPC neuroendocrine prostate cancer, DNPC double-negative CRPC.