Prostate cancer pathogenesis is dependent on signalling through the steroid nuclear hormone androgen receptor (AR), which is activated after binding of the androgen ligand testosterone or dihydrotestosterone. Ligand-bound AR translocates to the nucleus, where it serves to induce or repress gene expression through binding to chromatin at cis androgen response elements.
Medical castration to substantially deplete serum testosterone is the mainstay of therapy for advanced prostate cancer that recurs following surgical removal of the prostate (prostatectomy) or radiotherapy. However, castration therapy is not curative, and patients will eventually progress to lethal castration-resistant prostate cancer (CRPC).
Despite a castrate level of testosterone, CRPC almost uniformly remains dependent on AR signalling. Next-generation hormonal therapies for prostate cancer, abiraterone and enzalutamide, are now in widespread clinical use; abiraterone attacks AR signalling through inhibition of extra-gonadal androgen biosynthesis and enzalutamide interferes directly with androgen binding to AR.
Resistance mechanisms to these drugs have been identified that result in restoration of AR signalling through gain-of-function AR mutations, upregulation of constitutively active AR splice variants or increased intratumoural androgen biosynthesis. Another resistance mechanism bypasses AR by switching to the related glucocorticoid receptor (GR) to maintain transcriptional regulation of a subset of the same genes.
At resistance, a subset of patients are now presenting with low or no AR in their tumours, suggesting that evolution to complex genomic states completely independently of AR could increasingly become a cause for concern.
Comprehensive analyses of late-stage CRPC are uncovering multiple genetic lesions in this patient cohort that indicate that it may eventually be possible to stratify patients based on the genomic profile of their cancer. These efforts will aid in clinical trial design and facilitate the use of rationally designed combination strategies to improve patient outcomes.
During the past 10 years, preclinical studies implicating sustained androgen receptor (AR) signalling as the primary driver of castration-resistant prostate cancer (CRPC) have led to the development of novel agents targeting the AR pathway that are now in widespread clinical use. These drugs prolong the survival of patients with late-stage prostate cancer but are not curative. In this Review, we highlight emerging mechanisms of acquired resistance to these contemporary therapies, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence. This diverse range of resistance mechanisms presents new challenges for long-term disease control, which may be addressable through early use of combination therapies guided by recent insights from genomic landscape studies of CRPC.
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V.K.A. is funded by a Young Investigator Award from the Prostate Cancer Foundation and a Physician Research Training Award from the Department of Defense (W81XWH-11-1-0274). C.L.S. is funded by the Howard Hughes Medical Institute (SU2C/AACR (DT0712), by grants from the US National Cancer Institute (NCI) of the National Institutes of Health (NIH) (R01 CA155169-04, R01 CA19387-01 and T32 CA160001-05), NIH/NCI/Memorial Sloan Kettering Cancer Center (MSKCC) Spore in Prostate Cancer (P50 CA092629-14), and from the NCI/MSKCC Support Grant/Core Grant (P30 CA008748-49 and P30 CA008748-49 S2).
P.A.W. owns stock in Tokai Pharmaceuticals. C.L.S. is an inventor of patents covering enzalutamide and ARN-509 and is entitled to royalties. He also serves on the Board of Directors of Novartis. V.K.A. declares no competing interests.
- Prostate-specific antigen
(PSA). An androgen-regulated serine protease encoded by the gene KLK3, PSA is produced by epithelial cells of the normal and cancerous prostate. Serum levels of PSA are widely used in the clinic as a screening tool for prostate cancer, as well as to monitor cancer recurrence in the post-treatment setting.
Male sex steroid hormones, of which testosterone and dihydrotestosterone (DHT) are the principal examples, that bind to and activate the androgen receptor.
- Gonadotropin-releasing hormone
(GnRH). Additionally known as luteinizing hormone-releasing hormone (LHRH), GnRH is a small peptide hormone produced in the hypothalamus that stimulates the secretion of luteinizing hormone and follicle-stimulating hormone by the pituitary gland.
- Luteinizing hormone
(LH). Secreted by the pituitary gland in response to stimulation by gonadotropin-releasing hormone, LH in turn stimulates receptors on Leydig cells of the testes, which leads to synthesis and secretion of testosterone.
(Cytochrome P450 family 17 subfamily A polypeptide 1). CYP17A1 possesses both 17α-hydroxylase and 17, 20-lyase activities and is a key enzyme in the synthesis of steroid hormones.
A class of steroid hormones produced by the adrenal gland that are involved in the regulation of metabolism and possess anti-inflammatory activity. The physiological effects of glucocorticoids are mediated through the glucocorticoid receptor.
An antineoplastic taxane that disrupts microtubule disassembly, resulting in inhibition of mitosis. Docetaxel is approved for use in men with metastatic castration-resistant prostate cancer by the US Food and Drug Administration (FDA).
(Chromatin immunoprecipitation followed by sequencing). A technique to ascertain the cistrome of a transcription factor of interest through the use of immunoprecipitation followed by massive parallel sequencing.
The collection of DNA elements within a genome that are bound by a transcription factor.
A rare subtype of prostate cell found in both the normal and cancerous prostate, which is noted for the secretion of numerous neuropeptides.
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Watson, P., Arora, V. & Sawyers, C. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer 15, 701–711 (2015). https://doi.org/10.1038/nrc4016
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