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Cancers 2017, 9(6), 67; doi:10.3390/cancers9060067

Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance

1
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
2
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
3
Division of Hematology and Oncology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
*
Author to whom correspondence should be addressed.
Academic Editor: W. Martin Kast
Received: 13 April 2017 / Revised: 7 June 2017 / Accepted: 7 June 2017 / Published: 12 June 2017
View Full-Text   |   Download PDF [1774 KB, uploaded 12 June 2017]   |  

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. View Full-Text
Keywords: castration-resistant prostate cancer; androgen receptor; progression; resistance mechanisms; enzalutamide; abiraterone castration-resistant prostate cancer; androgen receptor; progression; resistance mechanisms; enzalutamide; abiraterone
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Crona, D.J.; Whang, Y.E. Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance. Cancers 2017, 9, 67.

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