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Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

Key Points

  • 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.

Abstract

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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Figure 1: AR signalling is regulated by the hypothalamic–pituitary–testicular axis, adrenal gland steroidogenesis and prostate cell intrinsic factors.
Figure 2: Overview of resistance mechanisms to next-generation AR-targeted therapies for CRPC.
Figure 3: Domain structure of AR, cancer-associated missense mutations and splice variants.
Figure 4: Opposing roles of glucocorticoids in prostate cancer.

References

  1. Haas, G. P., Delongchamps, N., Brawley, O. W., Wang, C. Y. & de la Roza, G. The worldwide epidemiology of prostate cancer: perspectives from autopsy studies. Can. J. Urol. 15, 3866–3871 (2008).

    PubMed  PubMed Central  Google Scholar 

  2. National Cancer Institute. SEER Stat Fact Sheets: Prostate Cancer National Cancer Institute [online], (2012).

  3. Buzzoni, C. et al. Metastatic prostate cancer incidence and prostate-specific antigen testing: new insights from the European Randomized Study of Screening for Prostate Cancer. Eur. Urol. 68, 885–890 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Huggins, C., Stevens, R. E. Jr & Hodges, C. V. Studies on prostatic cancer II. The effects of castration on advanced carcinoma of the prostate gland. Arch. Surg. 43, 209–223 (1941).

    Article  CAS  Google Scholar 

  5. van Poppel, H. & Nilsson, S. Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology 71, 1001–1006 (2008).

    Article  PubMed  Google Scholar 

  6. Visakorpi, T. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat. Genet. 9, 401–406 (1995). This was the first paper to establish that AR undergoes frequent genomic amplification in prostate cancer during progression to castration resistance.

    Article  CAS  PubMed  Google Scholar 

  7. Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10, 33–39 (2004). Modest overexpression of AR in prostate cancer cells was sufficient to confer resistance to AR inhibition, in part by facilitating the conversion of an anti-androgen into a transcriptional agonist.

    Article  CAS  PubMed  Google Scholar 

  8. Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Attard, G., Belldegrun, A. S. & de Bono, J. S. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 96, 1241–1246 (2005).

    Article  PubMed  Google Scholar 

  10. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012). In a Phase III trial, enzalutamide prolonged the survival of patients with metastatic CRPC refractory to docetaxel by nearly 5 months.

    Article  CAS  PubMed  Google Scholar 

  11. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011). In a Phase III trial, abiraterone conferred a nearly 4-month survival advantage to patients with metastatic CRPC refractory to docetaxel.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ryan, C. J. et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 16, 152–160 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Veldscholte, J. et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem. Biophys. Res. Commun. 173, 534–540 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Suzuki, H. et al. Androgen receptor gene mutations in human prostate cancer. J. Steroid Biochem. Mol. Biol. 46, 759–765 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Beltran, H. et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur. Urol. 63, 920–926 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015). A multi-institutional effort that generated whole-exome and transcriptome sequencing from 150 patients with metastatic CRPC. This study identified clinically actionable genomic alterations in 89% of the patients, highlighting possible avenues for personalized medicine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gottlieb, B., Beitel, L. K., Nadarajah, A., Paliouras, M. & Trifiro, M. The androgen receptor gene mutations database: 2012 update. Hum. Mutat. 33, 887–894 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Tan, J. et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol. Endocrinol. 11, 450–459 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Taplin, M. E. et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 59, 2511–2515 (1999).

    CAS  PubMed  Google Scholar 

  24. Scher, H. I. & Kelly, W. K. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J. Clin. Oncol. 11, 1566–1572 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Suzuki, H. et al. Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome. Prostate 29, 153–158 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Hara, T. et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 63, 149–153 (2003).

    CAS  PubMed  Google Scholar 

  27. Balbas, M. D. et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2, e00499 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Clegg, N. J. et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 72, 1494–1503 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Joseph, J. D. et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 3, 1020–1029 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Azad, A. A. et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin. Cancer Res. 21, 2315–2324 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Zhao, X. Y. et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat. Med. 6, 703–706 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. van de Wijngaart, D. J. et al. Systematic structure-function analysis of androgen receptor Leu701 mutants explains the properties of the prostate cancer mutant L701H. J. Biol. Chem. 285, 5097–5105 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Chen, E. J. et al. Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin. Cancer Res. 21, 1273–1280 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Carreira, S. et al. Tumor clone dynamics in lethal prostate cancer. Sci. Transl Med. 6, 254ra125 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Attard, G. et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J. Clin. Endocrinol. Metab. 97, 507–516 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Ware, K. E., Garcia-Blanco, M. A., Armstrong, A. J. & Dehm, S. M. Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer. Endocr. Relat. Cancer 21, T87–T103 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nakazawa, M., Antonarakis, E. S. & Luo, J. Androgen receptor splice variants in the era of enzalutamide and abiraterone. Horm. Cancer 5, 265–273 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L. & Tindall, D. J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 68, 5469–5477 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Watson, P. A. et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc. Natl Acad. Sci. USA 107, 16759–16765 (2010). Overexpression of ARVs in which the LBD was deleted was not sufficient to confer growth resistance to enzalutamide, suggesting that in certain cellular contexts the ARVs are not fully capable of recapitulating the function of the full-length receptor.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Guo, Z. et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 69, 2305–2313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hu, R. et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 69, 16–22 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sun, S. et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J. Clin. Invest. 120, 2715–2730 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hu, R., Isaacs, W. B. & Luo, J. A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. Prostate 71, 1656–1667 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jenster, G., Trapman, J. & Brinkmann, A. O. Nuclear import of the human androgen receptor. Biochem. J. 293, 761–768 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hornberg, E. et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS ONE 6, e19059 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Quarmby, V. E., Yarbrough, W. G., Lubahn, D. B., French, F. S. & Wilson, E. M. Autologous down-regulation of androgen receptor messenger ribonucleic acid. Mol. Endocrinol. 4, 22–28 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Shan, L. X., Rodriguez, M. C. & Janne, O. A. Regulation of androgen receptor protein and mRNA concentrations by androgens in rat ventral prostate and seminal vesicles and in human hepatoma cells. Mol. Endocrinol. 4, 1636–1646 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Yu, Z. et al. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin. Cancer Res. 20, 1590–1600 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cai, C. et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 20, 457–471 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu, L. L. et al. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene 33, 3140–3150 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Li, Y. et al. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 73, 483–489 (2013). In prostate cancer cells with naturally high expression of LBD-truncated ARVs and inherent anti-androgen resistance, variant-specific knockdown conferred sensitivity to enzalutamide.

    Article  CAS  PubMed  Google Scholar 

  52. Li, Y. et al. Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. Cancer Res. 71, 2108–2117 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, Y. et al. AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene 31, 4759–4767 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sun, F. et al. Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J. Biol. Chem. 289, 1529–1539 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Liu, G. et al. AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer. Neoplasia 15, 1009–1017 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Efstathiou, E. et al. Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur. Urol. 67, 53–60 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bramson, H. N. et al. Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J. Pharmacol. Exp. Ther. 282, 1496–1502 (1997).

    CAS  PubMed  Google Scholar 

  59. Steers, W. D. 5α reductase activity in the prostate. Urology 58 (6 Suppl. 1), 17–24.

  60. Nishiyama, T., Hashimoto, Y. & Takahashi, K. The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin. Cancer Res. 10, 7121–7126 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B. & Mohler, J. L. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11, 4653–4657 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Montgomery, R. B. et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68, 4447–4454 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Page, S. T. et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J. Clin. Endocrinol. Metab. 91, 3850–3856 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Tamae, D. et al. The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chem. Biol. Interact. 234, 332–338 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Dufort, I., Rheault, P., Huang, X. F., Soucy, P. & Luu-The, V. Characteristics of a highly labile human type 5 17β-hydroxysteroid dehydrogenase. Endocrinology 140, 568–574 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Koh, E., Noda, T., Kanaya, J. & Namiki, M. Differential expression of 17β-hydroxysteroid dehydrogenase isozyme genes in prostate cancer and noncancer tissues. Prostate 53, 154–159 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Chang, K. H. et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 108, 13728–13733 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Liu, C. et al. Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Res. 75, 1413–1422 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cai, C. et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 71, 6503–6513 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Adeniji, A. O., Chen, M. & Penning, T. M. AKR1C3 as a target in castrate resistant prostate cancer. J. Steroid Biochem. Mol. Biol. 137, 136–149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chang, K. H. et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074–1084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sawyers, C. L. in DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology (eds DeVita, V. T. D. Jr, Lawrence, T. S. & Rosenberg, S. A.) 237–247 (Wolters Kluwer Health, 2015).

    Google Scholar 

  73. Isikbay, M. et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm. Cancer 5, 72–89 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Arora, V. K. et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013). By acquiring expression of the GR, prostate cancer cells were shown to evade the antiproliferative effects of enzalutamide or ARN-509 by utilizing this related steroid hormone receptor to cross-regulate a subset of AR-regulated target genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1, 34–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Pienta, K. J. & Bradley, D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin. Cancer Res. 12, 1665–1671 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Sahu, B. et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res. 73, 1570–1580 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Efstathiou, E. et al. Biological heterogeneity in localized high-risk prostate cancer (LHRPC) from a study of neoadjuvant abiraterone acetate plus leuprolide acetate (LHRHa) versus LHRHa. J. Clin. Oncol. 33 (15 Suppl.), 5005 (2015).

    Article  Google Scholar 

  79. Tannock, I. et al. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J. Clin. Oncol. 7, 590–597 (1989).

    Article  CAS  PubMed  Google Scholar 

  80. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Song, L. N., Coghlan, M. & Gelmann, E. P. Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor. Mol. Endocrinol. 18, 70–85 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Taplin, M. E. et al. A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU Int. 101, 1084–1089 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Lu, N. Z. et al. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol. Rev. 58, 782–797 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Grindstad, T. et al. High progesterone receptor expression in prostate cancer is associated with clinical failure. PLoS ONE 10, e0116691 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bonkhoff, H., Fixemer, T., Hunsicker, I. & Remberger, K. Progesterone receptor expression in human prostate cancer: correlation with tumor progression. Prostate 48, 285–291 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Mobbs, B. G. & Liu, Y. Immunohistochemical localization of progesterone receptor in benign and malignant human prostate. Prostate 16, 245–251 (1990).

    Article  CAS  PubMed  Google Scholar 

  87. Yu, Y. et al. Expression and function of the progesterone receptor in human prostate stroma provide novel insights to cell proliferation control. J. Clin. Endocrinol. Metab. 98, 2887–2896 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Roudier, M. P. et al. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum. Pathol. 34, 646–653 (2003).

    Article  PubMed  Google Scholar 

  89. Shah, R. B. et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 64, 9209–9216 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hobisch, A. et al. Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res. 55, 3068–3072 (1995).

    CAS  PubMed  Google Scholar 

  92. Efstathiou, E. et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J. Clin. Oncol. 30, 637–643 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Crnalic, S. et al. Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients. Endocr. Relat. Cancer 17, 885–895 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Palmgren, J. S., Karavadia, S. S. & Wakefield, M. R. Unusual and underappreciated: small cell carcinoma of the prostate. Semin. Oncol. 34, 22–29 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Deorah, S., Rao, M. B., Raman, R., Gaitonde, K. & Donovan, J. F. Survival of patients with small cell carcinoma of the prostate during 1973-2003: a population-based study. BJU Int. 109, 824–830 (2012).

    Article  PubMed  Google Scholar 

  96. Epstein, J. I. et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol. 38, 756–767 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Tan, H. L. et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin. Cancer Res. 20, 890–903 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Beltran, H. et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1, 487–495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhou, Z. et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 66, 7889–7898 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Lotan, T. L. et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod. Pathol. 24, 820–828 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Guo, C. C. et al. TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate. Hum. Pathol. 42, 11–17 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Williamson, S. R. et al. ERG-TMPRSS2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder: evidence supporting monoclonal origin. Mod. Pathol. 24, 1120–1127 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Yuan, T. C., Veeramani, S. & Lin, M. F. Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocr. Relat. Cancer 14, 531–547 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Small, E. J. et al. Characterization of neuroendocrine prostate cancer (NEPC) in patients with metastatic castration resistant prostate cancer (mCRPC) resistant to abiraterone (Abi) or enzalutamide (Enz): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT). J. Clin. Oncol. 33 (15 Suppl.), 5003 (2015).

    Article  Google Scholar 

  106. Schrader, A. J. et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur. Urol. 65, 30–36 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Noonan, K. L. et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann. Oncol. 24, 1802–1807 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Badrising, S. et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 120, 968–975 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Zhang, T. et al. Exploring the clinical benefit of docetaxel or enzalutamide after disease progression during abiraterone acetate and prednisone treatment in men with metastatic castration-resistant prostate cancer. Clin. Genitourin. Cancer 13, 392–399 (2015).

    Article  PubMed  Google Scholar 

  110. Bianchini, D. et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur. J. Cancer 50, 78–84 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Brasso, K. et al. Enzalutamide antitumour activity against metastatic castration-resistant prostate cancer previously treated with docetaxel and abiraterone: a multicentre analysis. Eur. Urol. 68, 317–324 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Li, Z. et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523, 347–351 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Andersen, R. J. et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17, 535–546 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Dalal, K. et al. Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer. J. Biol. Chem. 289, 26417–26429 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Osborne, C. K., Wakeling, A. & Nicholson, R. I. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br. J. Cancer 90 (Suppl. 1), S2–S6 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Omlin, A. et al. AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies. Invest. New Drugs 33, 679–690 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Bitting, R. L. & Armstrong, A. J. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr. Relat. Cancer 20, R83–R99 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Schwartz, S. et al. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell 27, 109–122 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Sandhu, S. K. et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 14, 882–892 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Mateo, J. et al. DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. Cancer Res. 75, CT322 (2015).

    Google Scholar 

  126. Lohr, J. G. et al. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat. Biotechnol. 32, 479–484 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sramkoski, R. M. et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell. Dev. Biol. Anim. 35, 403–409 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Pretlow, T. G. et al. Xenografts of primary human prostatic carcinoma. J. Natl Cancer Inst. 85, 394–398 (1993).

    Article  CAS  PubMed  Google Scholar 

  130. Dagvadorj, A. et al. Androgen-regulated and highly tumorigenic human prostate cancer cell line established from a transplantable primary CWR22 tumor. Clin. Cancer Res. 14, 6062–6072 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Stone, K. R., Mickey, D. D., Wunderli, H., Mickey, G. H. & Paulson, D. F. Isolation of a human prostate carcinoma cell line (DU 145). Int. J. Cancer 21, 274–281 (1978).

    Article  CAS  PubMed  Google Scholar 

  132. Mitchell, S., Abel, P., Ware, M., Stamp, G. & Lalani, E. Phenotypic and genotypic characterization of commonly used human prostatic cell lines. BJU Int. 85, 932–944 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Klein, K. A. et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat. Med. 3, 402–408 (1997).

    Article  CAS  PubMed  Google Scholar 

  134. Horoszewicz, J. S. et al. The LNCaP cell line—a new model for studies on human prostatic carcinoma. Prog. Clin. Biol. Res. 37, 115–132 (1980).

    CAS  PubMed  Google Scholar 

  135. Horoszewicz, J. S. et al. LNCaP model of human prostatic carcinoma. Cancer Res. 43, 1809–1818 (1983).

    CAS  PubMed  Google Scholar 

  136. Wu, H. C. et al. Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int. J. Cancer 57, 406–412 (1994).

    Article  CAS  PubMed  Google Scholar 

  137. Navone, N. M. et al. Establishment of two human prostate cancer cell lines derived from a single bone metastasis. Clin. Cancer Res. 3, 2493–2500 (1997).

    CAS  PubMed  Google Scholar 

  138. Zhao, X. Y. et al. Two mutations identified in the androgen receptor of the new human prostate cancer cell line MDA PCa 2a. J. Urol. 162, 2192–2199 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Kaighn, M. E., Narayan, K. S., Ohnuki, Y., Lechner, J. F. & Jones, L. W. Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest. Urol. 17, 16–23 (1979).

    CAS  PubMed  Google Scholar 

  140. Korenchuk, S. et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 15, 163–168 (2001).

    CAS  PubMed  Google Scholar 

  141. Liu, W. et al. Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. Neoplasia 10, 897–907 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Georget, V. et al. Trafficking of the androgen receptor in living cells with fused green fluorescent protein-androgen receptor. Mol. Cell. Endocrinol. 129, 17–26 (1997).

    Article  CAS  PubMed  Google Scholar 

  143. Georget, V., Terouanne, B., Nicolas, J. C. & Sultan, C. Mechanism of antiandrogen action: key role of hsp90 in conformational change and transcriptional activity of the androgen receptor. Biochemistry 41, 11824–11831 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Wong, C. I., Zhou, Z. X., Sar, M. & Wilson, E. M. Steroid requirement for androgen receptor dimerization and DNA binding. Modulation by intramolecular interactions between the NH2-terminal and steroid-binding domains. J. Biol. Chem. 268, 19004–19012 (1993).

    CAS  PubMed  Google Scholar 

  145. Shang, Y., Myers, M. & Brown, M. Formation of the androgen receptor transcription complex. Mol. Cell 9, 601–610 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Wang, Q. et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol. Cell 27, 380–392 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sahu, B. et al. Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J. 30, 3962–3976 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Attard, G. et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J. Clin. Oncol. 27, 3742–3748 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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).

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Correspondence to Philip A. Watson or Charles L. Sawyers.

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Competing interests

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.

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Glossary

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.

Androgens

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.

CYP17A1

(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.

Glucocorticoids

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.

Docetaxel

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).

ChIP–seq

(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.

Cistrome

The collection of DNA elements within a genome that are bound by a transcription factor.

Neuroendocrine

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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