Abstract
Despite the initial efficacy of androgen deprivation in prostate cancer, virtually all patients progress to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling is critically required for CRPC. A new generation of medications targeting AR, such as abiraterone and enzalutamide, has improved survival of metastatic CRPC (mCRPC) patients. However, a significant proportion of patients presents with primary resistance to these agents, and in the remainder, secondary resistance will invariably develop, which makes mCRPC the lethal form of the disease. Mechanisms underlying progression to mCRPC and treatment resistance are extremely complex. AR-dependent resistance mechanisms include AR amplification, AR point mutations, expression of constitutively active AR splice variants, and altered intratumoral androgen biosynthesis. AR-independent resistance mechanisms include glucocorticoid receptor activation, immune-mediated resistance, and neuroendocrine differentiation. The development of novel agents, such as seviteronel, apalutamide, and EPI-001/EPI-506, as well as the identification and validation of novel predictive biomarkers of resistance, may lead to improved therapeutics for mCRPC patients.
Highlights
In the United States, prostate cancer is the most commonly diagnosed malignancy, where approximately one out of every seven men will be diagnosed with the disease during their lifetime [1]
AFFIRM met its primary endpoint by demonstrating that median Overall survival (OS) was 4.8 months longer in patients treated with enzalutamide (18.4 versus 13.6 months), and the risk of death was decreased by 37%, when compared to placebo (HR = 0.63; 95% CI, 0.53–0.75; p < 0.001)
This study demonstrated that JQ1 effectively inhibited Androgen receptor (AR)-V7 and ARv567es mRNA and protein expression [82]
Summary
In the United States, prostate cancer is the most commonly diagnosed malignancy (aside from skin cancer), where approximately one out of every seven men will be diagnosed with the disease during their lifetime [1]. Some patients (perhaps up to 20–30%) with clinically localized prostate cancer will have recurrence of their disease after treatment and will progress to the metastatic stage over time. Despite its initial effectiveness in stabilizing or causing regression of metastatic prostate cancer, progression to the lethal form of the disease, known as castration-resistant prostate cancer (CRPC), is essentially inevitable for these patients. Mechanisms that alter AR axis signaling, disease progression, and/or lead to treatment resistance in CRPC can be stratified into AR-dependent and AR-independent resistance mechanisms. Metastatic CRPC (mCRPC) remains incurable, and novel treatment resistance mechanisms continue to be identified, implicating numerous, complex dysregulated molecular signaling pathways that underlie the progression and lethality of the disease. The primary objective of this review article is to discuss the etiologies underlying clinically-relevant mechanisms that lead to drug resistance in mCRPC, and the potential treatment strategies designed to overcome resistance
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