Journal
CANCER DRUG RESISTANCE
Volume 3, Issue 4, Pages 912-929Publisher
OAE PUBLISHING INC
DOI: 10.20517/cdr.2020.60
Keywords
Prostate cancer; abiraterone acetate; enzalutamide; aldo-keto reductase 1C3; androgen biosynthesis
Categories
Funding
- National Institute of Environmental Health Science [P30ES013508]
- National Cancer Institute [W81XWH-17-1-0404, R01CA249210]
- Department of Defense Prostate Cancer Research Program [W81XWH-17-1-0484, W81XWH-17-2-0323, W81XWH-20-1-0146]
- Lopker Foundation
- Veterans Affairs Research Program
- Institute for Prostate Cancer Research
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Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use AR signaling inhibitors (ARSI) exemplified by abiraterone acetate, a P450c17 inhibitor, and enzalutamide, a potent AR antagonist. However, drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months. Multiple mechanisms can contribute to ARSI drug resistance. These mechanisms can include but are not limited to germline mutations in the AR, post-transcriptional alterations in AR structure, and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor. This review focuses on intracrine androgen biosynthesis, how this can contribute to ARSI drug resistance, and therapeutic strategies that can be used to surmount these resistance mechanisms.
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