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Current Urology Reports

, 17:29 | Cite as

Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer

  • John L. Silberstein
  • Maritza N. Taylor
  • Emmanuel S. Antonarakis
Prostate Cancer (A Kibel, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Prostate Cancer

Abstract

While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling. Nevertheless, additional androgen-pathway resistance usually develops to these novel hormonal therapies. In this review, we will discuss the resistance mechanisms to modern androgen-axis modulators and how these alterations can influence a patient’s response to novel hormonal therapy. We conceptualize these resistance pathways as three broad categories: (1) reactivation of androgen/AR-signaling, (2) AR bypass pathways, and (3) androgen/AR-independent mechanisms. We highlight examples of each, as well as potential therapeutic approaches to overcome these resistance mechanisms.

Keywords

Prostate cancer Androgen receptor Splice variants Resistance Biomarker 

Abbreviations

ADT

androgen deprivation therapy

AR

androgen receptor

ARE

androgen response element

AR-FL

full-length androgen receptor

AR-V

androgen receptor splice variant

cfDNA

cell-free DNA

CRPC

castration-resistant prostate cancer

CTC

circulating tumor cell

CYP17A1

cytochrome P450 17A1

DBD

DNA-binding domain

DHT

dihydrotestosterone

GR

glucocorticoid receptor

HSPC

hormone-sensitive prostate cancer

LBD

ligand-binding domain

NTD

N-terminal domain

PFS

progression-free survival

PR

progesterone receptor

OS

overall survival

Notes

Compliance with Ethical Standards

Conflict of Interest

John L. Silberstein and Maritza N. Taylor declare no potential conflicts of interest. Emmanuel S. Antonarakis has served as a paid consultant/advisor for Janssen, Astellas, Sanofi, Dendreon, Essa, and Medivation; he has received research funding from Janssen, Johnson & Johnson, Sanofi, Dendreon, Exelixis, Genentech, Novartis, and Tokai; he is a co-inventor of a technology that has been licensed to Tokai.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance.•• Of major importance

  1. 1.
    Howlander N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al. SEER Cancer Statistics Review, 1975–2012. 2015; Available from: http://seer.cancer.gov/csr/1975_2012/.Google Scholar
  2. 2.
    Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737–46.Google Scholar
  3. 3.
    Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983–92.Google Scholar
  4. 4.
    Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.Google Scholar
  5. 5.
    Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol. 2002;20:3001–15.CrossRefPubMedGoogle Scholar
  6. 6.
    Gao W, Bohl CE, Dalton JT. Chemistry and structural biology of androgen receptor. Chem Rev. 2005;105:3352–70.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Egan A, Dong Y, Zhang H, Qi Y, Balk SP, Sartor O. Castration-resistant prostate cancer: adaptive responses in the androgen axis. Cancer Treat Rev. 2014;40:426–33.Google Scholar
  8. 8.
    Gordon V, Bhadel S, Wunderlich W, Zhang J, Ficarro SB, Mollah SA, et al. CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol. 2010;24:2267–80.Google Scholar
  9. 9.••
    Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309–22. This article is one of the first studies to show the clinical relevance of GR in prostate cancer, especially in the setting of enzalutamide resistance.Google Scholar
  10. 10.
    Carreira S, Romanel A, Goodall J, Grist E, Ferraldeschi R, Miranda S, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6:254ra125.Google Scholar
  11. 11.
    Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, Doshi S, et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 2013;3:1030–43.Google Scholar
  12. 12.
    Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3:1020–9.Google Scholar
  13. 13.
    Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA, et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife. 2013;2:e00499.Google Scholar
  14. 14.•
    Azad AA, Volik SV, Wyatt AW, Haegert A, Le Bihan S, Bell RH, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 2015;21:2315–24. This study showed the feasibility and prognostic impact of using cfDNA as a biomarker to analyze androgen receptor copy number variations and mutations.Google Scholar
  15. 15.
    Romanel A, Tandefelt DG, Conteduca V, Jayaram A, Casiraghi N, Wetterskog D, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;7:312re10.Google Scholar
  16. 16.
    Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature. 2015;523:347–51.Google Scholar
  17. 17.
    Li R, Evaul K, Sharma KK, Chang KH, Yoshimoto J, Liu J, et al. Abiraterone inhibits 3beta-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res. 2012;18:3571–9.Google Scholar
  18. 18.
    Salvi S, Casadio V, Conteduca V, Burgio SL, Menna C, Bianchi E, et al. Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone. Br J Cancer. 2015;112:1717–24.Google Scholar
  19. 19.
    Lin HK, Jez JM, Schlegel BP, Peehl DM, Pachter JA, Penning TM. Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution. Mol Endocrinol. 1997;11:1971–84.Google Scholar
  20. 20.
    Liu C, Lou W, Zhu Y, Yang JC, Nadiminty N, Gaikwad NW, et al. Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Res. 2015;75:1413–22.Google Scholar
  21. 21.
    Tamae D, Mostaghel E, Montgomery B, Nelson PS, Balk SP, Kantoff PW, 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. 2015;234:332–8.Google Scholar
  22. 22.
    Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell. 2013;154:1074–84.Google Scholar
  23. 23.
    Hearn JWD, AbuAli G, Magi-Galluzzi C, Reddy CA, Chang KH, Klein EA, et al. HSD3B1 and resistance to androgen deprivation therapy in prostate cancer. J Clin Oncol. 2015;33 suppl 7:abstr 156.Google Scholar
  24. 24.
    Kwegyir-Afful AK, Senthilmurugan R, Purushottamachar P, Ramamurthy VP, Njar VC. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. Oncotarget. 2015;6:27440–60.Google Scholar
  25. 25.
    Zhang X, Hong SZ, Lin EJ, Wang DY, Li ZJ, Chen LI. Amplification and protein expression of androgen receptor gene in prostate cancer cells: fluorescence hybridization analysis. Oncol Lett. 2015;9:2617–22.Google Scholar
  26. 26.
    Efstathiou E, Titus M, Wen S, Hoang A, Karlou M, Ashe R, et al. Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol. 2015;67:53–60.Google Scholar
  27. 27.
    Zhao XY, Malloy PJ, Krishnan AV, Swami S, Navone NM, Peehl DM, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000;6:703–6.Google Scholar
  28. 28.
    Steketee K, Timmerman L, Ziel-van der Made AC, Doesburg P, Brinkmann AO, Trapman J. Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer. Int J Cancer. 2002;100:309–17.Google Scholar
  29. 29.
    Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, et al. Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res. 2015;21:1273–80.Google Scholar
  30. 30.
    Rathkopf DE, Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, et al. Androgen receptor mutations in patients with castration-resistant prostate cancer with and without prior abiraterone acetate treatment. AACR Annual Meeting. 2015. Philadelphia, PA: Cancer Res. 75(15 suppl):abstr CT134Google Scholar
  31. 31.
    Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.Google Scholar
  32. 32.
    Fizazi K, Massard C, Bono P, Jones R, Kataja V, James N, et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 2014;15:975–85.Google Scholar
  33. 33.
    Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16–22.Google Scholar
  34. 34.••
    Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28. This study is one of the most comprehensive genomic analyses of castration-resistant prostate cancer.Google Scholar
  35. 35.
    Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 2014;33:3140–50.Google Scholar
  36. 36.
    Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72:3457–62.Google Scholar
  37. 37.
    Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010;120:2715–30.Google Scholar
  38. 38.
    Hornberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One. 2011;6:e19059.Google Scholar
  39. 39.
    Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, et al. Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep. 2015;5:7654.Google Scholar
  40. 40.
    Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69:2305–13.Google Scholar
  41. 41.••
    Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–38. This study showed that AR-V7 might be a clinically relevant biomarker for enzalutamide and abiraterone resistance that can be tested from CTCs through non-invasive means.Google Scholar
  42. 42.
    Steinestel J, Luedeke M, Arndt A, Schnoeller TJ, Lennerz JK, Wurm C, et al. Detecting predictive androgen receptor modifications in circulating prostate cancer cells. Oncotarget. 2015.Google Scholar
  43. 43.
    Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1:582–91.Google Scholar
  44. 44.
    Onstenk W, Sieuwerts AM, Kraan J, Van M, Nieuweboer AJ, Mathijssen RH, et al. Efficacy of cabazitaxel in castration-resistant prostate cancer is independent of the presence of AR-V7 in circulating tumor cells. Eur Urol. 2015;68:939–45.Google Scholar
  45. 45.
    Nakazawa M, Lu C, Chen Y, Paller CJ, Carducci MA, Eisenberger MA, et al. Serial blood-based analysis of AR-V7 in men with advanced prostate cancer. Ann Oncol. 2015;26:1859–65.Google Scholar
  46. 46.
    Scher HI, Fizazi K, Saad F, Chi KN, Taplin ME, Sternberg CN, et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide, an androgen receptor inhibitor. J Clin Oncol. 2013;31 suppl 6:abstr 6.Google Scholar
  47. 47.
    Xie N, Cheng H, Lin D, Liu L, Yang O, Jia L, et al. The expression of glucocorticoid receptor is negatively regulated by active androgen receptor signaling in prostate tumors. Int J Cancer. 2015;136:E27–38.Google Scholar
  48. 48.
    Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC, Richardson RL. Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer. 1995;76:96–100.Google Scholar
  49. 49.
    Nishimura K, Nonomura N, Yasunaga Y, Takaha N, Inoue H, Sugao H, et al. Low doses of oral dexamethasone for hormone-refractory prostate carcinoma. Cancer. 2000;89:2570–6.Google Scholar
  50. 50.
    Shamash J, Powles T, Sarker SJ, Protheroe A, Mithal N, Mills R, et al. A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol. Br J Cancer. 2011;104:620–8.Google Scholar
  51. 51.
    Venkitaraman R, Thomas K, Huddart RA, Horwich A, Dearnaley DP, Parker CC. Efficacy of low-dose dexamethasone in castration-refractory prostate cancer. BJU Int. 2008;101:440–3.Google Scholar
  52. 52.
    Miyahira AK, Simons JW, Soule HR. The 20th Annual Prostate Cancer Foundation Scientific Retreat report. Prostate. 2014;74:811–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Grindstad T, Andersen S, Al-Saad S, Donnem T, Kiselev Y, Nordahl Melbo-Jorgensen C, et al. High progesterone receptor expression in prostate cancer is associated with clinical failure. PLoS One. 2015;10:e0116691.Google Scholar
  54. 54.
    Mateo J, Nowakowska K, Jayaram A, Rodrigues DN, Riisnaes R, Zukiwski A, et al. Phase 1 study of onapristone, a progesterone receptor (PR) antagonist, in castration-resistant prostate cancer. Prostate Cancer Foundation Scientific Retreat. 2014. Carlsbad, CA. abstract 60.Google Scholar
  55. 55.
    Zukiwski A, Bosq J, Gilles EM, Belldegrun A. Progesterone receptor (PR), a potential mechanism of resistance and target in AIPC. Prostate Cancer Foundation Scientific Retreat. 2014. abstract 47.Google Scholar
  56. 56.
    Mateo J, Rodrigues DN, Lopez RP, Flohr P, Riisnaes R, Lokiec FM, et al. A phase 1–2 study of the type I progesterone receptor (PR) antagonist, onapristone, in patients with advanced castration-resistant prostate cancer. ASCO Annual Meeting. 2014. J Clin Oncol. abstract TPS5097.Google Scholar
  57. 57.
    Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res. 2014;20:890–903.Google Scholar
  58. 58.
    Mithal P, Allott E, Gerber L, Reid J, Welbourn W, Tikishvili E, et al. PTEN loss in biopsy tissue predicts poor clinical outcomes in prostate cancer. Int J Urol. 2014;21:1209–14.Google Scholar
  59. 59.
    Mulholland DJ, Kobayashi N, Ruscetti M, Zhi A, Tran LM, Huang J, et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 2012;72:1878–89.Google Scholar
  60. 60.•
    Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science. 2015;349:1351–6. This study was the first to accomplish single-cell RNA sequencing and uncovered a new potential mechanism of enzalutamide resistance related to non-canonical Wnt signaling.Google Scholar
  61. 61.
    Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18:1359–68.Google Scholar
  62. 62.
    Mosquera JM, Beltran H, Park K, MacDonald TY, Robinson BD, Tagawa ST, et al. Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia. 2013;15:1–10.Google Scholar
  63. 63.
    Beltran H. The N-myc oncogene: maximizing its targets, regulation, and therapeutic potential. Mol Cancer Res. 2014;12:815–22.CrossRefPubMedGoogle Scholar
  64. 64.
    Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. 2015;67:470–9.Google Scholar
  65. 65.
    Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, et al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20:2846–50.Google Scholar
  66. 66.
    Feng FY, de Bono JS, Rubin MA, Knudsen KE. Chromatin to clinic: the molecular rationale for PARP1 inhibitor function. Mol Cell. 2015;58:925–34.Google Scholar
  67. 67.••
    Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708. This study showed the first potential genetic signature predicting response to the PARP inhibitor, olaparib, in men with CRPC.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • John L. Silberstein
    • 1
  • Maritza N. Taylor
    • 1
  • Emmanuel S. Antonarakis
    • 2
  1. 1.Brady Urological Institute, Department of UrologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA

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