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Review
. 2016 Mar 16;10(Suppl 1):1-9.
doi: 10.4137/CMO.S34534. eCollection 2016.

Resistance to Novel Antiandrogen Therapies in Metastatic Castration-Resistant Prostate Cancer

Karim Boudadi  1 , Emmanuel S Antonarakis  1
Affiliations
Review

Resistance to Novel Antiandrogen Therapies in Metastatic Castration-Resistant Prostate Cancer

Karim Boudadi et al. Clin Med Insights Oncol. .

Abstract

Despite the introduction of novel therapies that maximally decrease androgen-receptor (AR) signaling activity, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Even though abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC and have demonstrated significant survival benefits, a significant proportion of patients have primary resistance to these agents and virtually all patients develop secondary resistance. While the mechanisms of resistance to these agents are not fully understood, many hypotheses of AR-dependent and AR-independent mechanisms are emerging, including upregulation of AR and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptor, activation of alternative oncogenic signaling pathways, neuroendocrine transformation, and immune evasion via programmed death-ligand 1 upregulation. The aim of this review is to summarize the most clinically relevant mechanisms of resistance to novel androgen-directed agents, focusing on escape from enzalutamide and abiraterone.

Keywords: abiraterone; castration-resistant prostate cancer; enzalutamide; novel androgen-directed therapy; resistance.

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Figures

Figure 1.
Figure 1.
Mechanisms of resistance to novel antiandrogens: (A) AR and CYP17 upregulation, (B) AR splice variants, (C) AR point mutations, (D) GR upregulation, (E) alternative oncogenic signaling pathways, and (F) PD-L1/PD-1 upregulation. AR, androgen receptor; DHT, dihydrotestosterone; GR, glucocorticoid receptor.
See this image and copyright information in PMC

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