Skip to main content

Advertisement

Log in

Mechanisms of Therapeutic Resistance in Prostate Cancer

  • Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing and combinations. This review outlines our current understanding of mechanisms of therapeutic resistance in progression to and after the development of castration resistance, highlighting targetable and reversible mechanisms of resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

ADT:

Androgen deprivation therapy

CRPC:

Castration-resistant prostate cancer

EMT:

Epithelial-mesenchymal transition

MET:

Mesenchymal-epithelial transition

ECM:

Extracellular matrix

TGF-β:

Transforming growth factor β

LBD:

Ligand binding domain

AR:

Androgen Receptor

PTEN:

Phosphatase and tensin homolog deleted on chromosome ten

References

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

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  2. Huggins C, Stevens Jr RE, Hodges CV. Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209–23.

    Article  CAS  Google Scholar 

  3. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA. 2005;294:238–44.

    Article  CAS  PubMed  Google Scholar 

  4. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol. 2009;6:76–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332:1393–8.

    Article  CAS  PubMed  Google Scholar 

  6. Higano CS, Crawford ED. New and emerging agents for the treatment of castration-resistant prostate cancer. Urol Oncol. 2011;29:S1–8.

    Article  CAS  PubMed  Google Scholar 

  7. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 2001;61:4315–9.

    CAS  PubMed  Google Scholar 

  8. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Scher HI, Fizazi K, Saad F, Taplin M-E, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.

    Article  CAS  PubMed  Google Scholar 

  10. Halabi S, Lin C-Y, Kelly WK, Fizazi KS, Moul JW, Kaplan EB, et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32:671–7.

    Article  PubMed  PubMed Central  Google Scholar 

  11. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–54.

    Article  PubMed  CAS  Google Scholar 

  12. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.

    Article  CAS  PubMed  Google Scholar 

  13. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.

    Article  CAS  PubMed  Google Scholar 

  14. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12.

    Article  CAS  PubMed  Google Scholar 

  15. Valenca LB, Sweeney CJ, Pomerantz MM. Sequencing current therapies in the treatment of metastatic prostate cancer. Cancer Treat Rev. 41:332–40.

  16. Sartor O, Gillessen S. Treatment sequencing in metastatic castrate-resistant prostate cancer. Asian Journal of Andrology. 2014;16:426–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. van Soest RJ, de Morree ES, Kweldam CF, de Ridder CM, Wiemer EA, Mathijssen RH, et al. Targeting the androgen receptor confers in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in castration-resistant prostate cancer. Eur Urol. 2015;67:981–5.

    Article  PubMed  CAS  Google Scholar 

  18. Azad AA, Eigl BJ, Murray RN, Kollmannsberger C, Chi KN. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. Eur Urol. 2015;67:23–9.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang T, Dhawan MS, Healy P, George DJ, Harrison MR, Oldan J, 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. Clinical Genitourinary Cancer. 2015;13:392–9.

    Article  PubMed  Google Scholar 

  20. Paller CJ, Antonarakis ES. Management of biochemically recurrent prostate cancer after local therapy: evolving standards of care and new directions. Clinical Advances in Hematology & Oncology: H&O. 2013;11:14–23.

    Google Scholar 

  21. Agus DB, Cordon-Cardo C, Fox W, Drobnjak M, Koff A, Golde DW, et al. Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst. 1999;91:1869–76.

    Article  CAS  PubMed  Google Scholar 

  22. Yun EJ, Zhou J, Lin CJ, Hernandez E, Fazli L, Gleave M, et al. Targeting cancer stem cells in castration-resistant prostate cancer. Clinical Cancer Research. 2016;22:670–9.

    Article  CAS  PubMed  Google Scholar 

  23. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253–61.

    Article  CAS  PubMed  Google Scholar 

  24. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–6.

    Article  CAS  PubMed  Google Scholar 

  25. Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314–9.

    CAS  PubMed  Google Scholar 

  26. Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, et al. Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res. 1999;59:803–6.

    CAS  PubMed  Google Scholar 

  27. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.

    Article  PubMed  CAS  Google Scholar 

  28. Rodriguez-Vida A, Bianchini D, Van Hemelrijck M, Hughes S, Malik Z, Powles T, et al. Is there an antiandrogen withdrawal syndrome with enzalutamide? BJU Int. 2015;115:373–80.

    Article  CAS  PubMed  Google Scholar 

  29. Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003;63:149–53.

    CAS  PubMed  Google Scholar 

  30. Bohl CE, Miller DD, Chen J, Bell CE, Dalton JT. Structural basis for accommodation of nonsteroidal ligands in the androgen receptor. J Biol Chem. 2005;280:37747–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bohl CE, Gao W, Miller DD, Bell CE, Dalton JT. Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc Natl Acad Sci U S A. 2005;102:6201–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell. 138:245–56.

  34. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate-resistance and novel therapeutic approaches. Oncogene. 2013;32:5501–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jin RJ, Lho Y, Connelly L, Wang Y, Yu X, Saint Jean L, et al. The nuclear factor-kappaB pathway controls the progression of prostate cancer to androgen-independent growth. Cancer Res. 2008;68:6762–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang L, Altuwaijri S, Deng F, Chen L, Lal P, Bhanot UK, et al. NF-kappaB regulates androgen receptor expression and prostate cancer growth. Am J Pathol. 2009;175:489–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jin R, Yi Y, Yull FE, Blackwell TS, Clark PE, Koyama T, et al. NF-kappaB gene signature predicts prostate cancer progression. Cancer Res. 2014;74:2763–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mulholland David J, Tran Linh M, Li Y, Cai H, Morim A, Wang S, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell. 2011;19:792–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Edlind MP, Hsieh AC. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian Journal of Andrology. 2014;16:378–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res. 1994;54:5474–8.

    CAS  PubMed  Google Scholar 

  43. Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 2007;28:778–808.

    Article  CAS  PubMed  Google Scholar 

  44. Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther. 2013;140:223–38.

    Article  CAS  PubMed  Google Scholar 

  45. Yeh S, Miyamoto H, Shima H, Chang C. From estrogen to androgen receptor: a new pathway for sex hormones in prostate. Proc Natl Acad Sci U S A. 1998;95:5527–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ni L, Yang CS, Gioeli D, Frierson H, Toft DO, Paschal BM. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol. 2010;30:1243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Groner Anna C, Cato L, de Tribolet-Hardy J, Bernasocchi T, Janouskova H, Melchers D, et al. TRIM24 is an oncogenic transcriptional activator in prostate cancer. Cancer Cell. 29:846–58.

  48. Suzman DL, Antonarakis ES. Does degree of androgen suppression matter in hormone-sensitive. Journal of Clinical Oncology. 2015;33:1098–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nishiyama T, Hashimoto Y, Takahashi K. The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. American Association for Cancer Research. 2004;10:7121–6.

    CAS  Google Scholar 

  50. Mohler JL, Gregory CW, Ford 3rd OH, Kim D, Weaver CM, Petrusz P, et al. The androgen axis in recurrent prostate cancer. Clinical Cancer Research. 2004;10:440–8.

    Article  CAS  PubMed  Google Scholar 

  51. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clinical Cancer Research. 2005;11:4653–7.

    Article  CAS  PubMed  Google Scholar 

  52. Chang K, Ercole CE, Sharifi N. Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences. Br J Cancer. 2014;111:1249–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815–25.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhu H, Garcia JA. Targeting the adrenal gland in castration-resistant prostate cancer: a case for orteronel, a selective CYP-17 17,20-lyase inhibitor. Curr Oncol Rep. 2013;15:105–12.

    Article  CAS  PubMed  Google Scholar 

  57. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407–15.

    Article  CAS  PubMed  Google Scholar 

  58. Corn PG. The tumor microenvironment in prostate cancer: elucidating molecular pathways for therapy development. Cancer Manag Res. 2012;4:183–93.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Sun Y, Wang B-E, Leong KG, Yue P, Li L, Jhunjhunwala S, et al. Androgen deprivation causes epithelial–mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res. 2012;72:527–36.

    Article  CAS  PubMed  Google Scholar 

  60. Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28:15–33.

    Article  PubMed  Google Scholar 

  61. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

    Article  CAS  PubMed  Google Scholar 

  62. Zhu M-L, Kyprianou N. Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB J. 2010;24:769–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ouyang G, Wang Z, Fang X, Liu J, Yang CJ. Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells. Cellular and Molecular Life Sciences: CMLS. 2010;67:2605–18.

    Article  CAS  PubMed  Google Scholar 

  64. van der Pluijm G. Epithelial plasticity, cancer stem cells and bone metastasis formation. Bone. 2011;48:37–43.

    Article  PubMed  CAS  Google Scholar 

  65. Nakazawa M, Kyprianou N. Epithelial-mesenchymal-transition regulators in prostate cancer: androgens and beyond. J Steroid Biochem Mol Biol. 2016;166:84–90.

    Article  PubMed  CAS  Google Scholar 

  66. Jaggi M, Nazemi T, Abrahams NA, Baker JJ, Galich A, Smith LM, et al. N-cadherin switching occurs in high Gleason grade prostate cancer. Prostate. 2006;66:193–9.

    Article  CAS  PubMed  Google Scholar 

  67. Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 2007;13:7003–11.

    Article  CAS  PubMed  Google Scholar 

  68. Nouri M, Ratther E, Stylianou N, Nelson CC, Hollier BG, Williams ED. Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention. Frontiers in Oncology. 2014;4

  69. Kyprianou N. Molecular exploitation of apoptosis pathways in prostate cancer: World Scientific; 2012.

  70. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 144:646–74.

  71. Zielinski RR, Eigl BJ, Chi KN. Targeting the apoptosis pathway in prostate cancer. Cancer Journal. 2013;19:79–89.

    Article  CAS  Google Scholar 

  72. Denmeade SR, Lin XS, Isaacs JT. Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate. 1996;28:251–65.

    Article  CAS  PubMed  Google Scholar 

  73. Isaacs JT. Apoptosis: translating theory to therapy for prostate cancer. J Natl Cancer Inst. 2000;92:1367–9.

    Article  CAS  PubMed  Google Scholar 

  74. McKenzie S, Kyprianou N. Apoptosis evasion: the role of survival pathways in prostate cancer progression and therapeutic resistance. J Cell Biochem. 2006;97:18–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kajiwara T, Takeuchi T, Ueki T, Moriyama N, Ueki K, Kakizoe T, et al. Effect of Bcl-2 overexpression in human prostate cancer cells in vitro and in vivo. Int J Urol. 1999;6:520–5.

    Article  CAS  PubMed  Google Scholar 

  76. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clinical Cancer Research. 2009;15:1126–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rennebeck G, Martelli M, Kyprianou N. Anoikis and survival connections in the tumor microenvironment: is there a role in prostate cancer metastasis? Cancer Res. 2005;65:11230–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13:555–62.

    Article  CAS  PubMed  Google Scholar 

  79. Zheng DQ, Woodard AS, Fornaro M, Tallini G, Languino LR. Prostatic carcinoma cell migration via alpha(v)beta3 integrin is modulated by a focal adhesion kinase pathway. Cancer Res. 1999;59:1655–64.

    CAS  PubMed  Google Scholar 

  80. •• 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. The first evidence to suggest that the AR mutation F876L confers agonist properties to enzalutamide. While several activating mutations have been identified in the context of first-generation antiandrogens, this is the first mutation to be identified in a second-generation antiandrogen.

    Article  CAS  PubMed  Google Scholar 

  81. Lallous N, Volik SV, Awrey S, Leblanc E, Tse R, Murillo J, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 2016;17.

  82. Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP, et al. NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther. 2013;12:1629–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. •• Antonarakis ES, Lu C, Luber B, et al. ANdrogen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncology. 2015;1:582–91. This follow-up study showed that the presence of AR-V7 does not predict a response to taxane chemotherapies, challenging the predictive value of AR-V7 as a treatment selection biomarker for therapeutic resistance to non-antiandrogen treatments in CRPC.

    Article  PubMed  PubMed Central  Google Scholar 

  84. •• 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. Clinical evidence defining the association of AR splice variant-7 (AR-V7) with therapeutic resistance to abiraterone and enzalutamide in men with CRPC.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

  86. Thadani-Mulero M, Nanus DM, Giannakakou P. Androgen receptor on the move: boarding the microtubule expressway to the nucleus. Cancer Res. 2012;72:4611–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM, Kyprianou N. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res. 2010;70:7992–8002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lu Q, Luduena RF. Removal of beta III isotype enhances taxol induced microtubule assembly. Cell Struct Funct. 1993;18:173–82.

    Article  CAS  PubMed  Google Scholar 

  89. Duran GE, Wang YC, Francisco EB, Rose JC, Martinez FJ, Coller J, et al. Mechanisms of resistance to cabazitaxel. Mol Cancer Ther. 2015;14:193–201.

    Article  CAS  PubMed  Google Scholar 

  90. Puhr M, Hoefer J, Schafer G, Erb HH, Oh SJ, Klocker H, et al. Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205. Am J Pathol. 2012;181:2188–201.

    Article  CAS  PubMed  Google Scholar 

  91. Paller CJ, Antonarakis ES. Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Drug Design, Development and Therapy. 2011;5:117–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Nakazawa M, Antonarakis ES, Luo J. Androgen receptor splice variants in the era of enzalutamide and abiraterone. Hormones & Cancer. 2014;5:265–73.

    Article  CAS  Google Scholar 

  93. Dehm SM, Tindall DJ. Alternatively spliced androgen receptor variants. Endocrine-Related Cancer. 2011;18:R183–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. A novel androgen receptor splice variant is upregulated during prostate cancer progression and promotes androgen-depletion-resistant growth. Cancer Res. 2009;69:2305–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hu R, Isaacs WB, Luo J. A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. Prostate. 2011;71:1656–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013;73:483–9.

    Article  CAS  PubMed  Google Scholar 

  98. Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clinical Cancer Research. 2011;17:5913–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Carlin BI, Andriole GL. The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer. 2000;88:2989–94.

    Article  CAS  PubMed  Google Scholar 

  100. Logothetis CJ, Lin S-H. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 2005;5:21–8.

    Article  CAS  PubMed  Google Scholar 

  101. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002;168:1005–7.

    Article  PubMed  Google Scholar 

  102. Halabi S, Vogelzang NJ, Kornblith AB, Ou SS, Kantoff PW, Dawson NA, et al. Pain predicts overall survival in men with metastatic castration-refractory prostate cancer. Journal of Clinical Oncology. 2008;26:2544–9.

    Article  PubMed  Google Scholar 

  103. Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, et al. Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res. 2012;72:2473–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Smith MR, Coleman RE, Klotz L, Pittman K, Milecki P, Ng S, et al. Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events. Ann Oncol. 2015;26:368–74.

    Article  CAS  PubMed  Google Scholar 

  105. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39–46.

    Article  CAS  PubMed  Google Scholar 

  106. Chu GCY, Zhau HE, Wang R, Rogatko A, Feng X, Zayzafoon M, et al. RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocrine-related cancer. 2014;21:311–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. El-Amm J, Aragon-Ching JB. Targeting bone metastases in metastatic castration-resistant prostate cancer. Clinical Medicine Insights Oncology. 2016;10:11–9.

    PubMed  PubMed Central  Google Scholar 

  108. Ning Y-M, Brave M, Maher VE, Zhang L, Tang S, Sridhara R, et al. U.S. Food and Drug Administration approval summary: enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. Oncologist. 2015;20:960–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Buttigliero C, Tucci M, Bertaglia V, Vignani F, Bironzo P, Di Maio M, et al. Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer. Cancer Treat Rev. 2015;41:884–92.

    Article  CAS  PubMed  Google Scholar 

  111. 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.

    Article  CAS  PubMed  Google Scholar 

  112. Arora Vivek K, Schenkein E, Murali R, Subudhi Sumit K, Wongvipat J, Balbas Minna D, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. Journal of Clinical Oncology. 2008;26:4563–71.

    Article  CAS  PubMed  Google Scholar 

  114. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.

    Article  CAS  PubMed  Google Scholar 

  115. Attard G, Reid AH, Auchus RJ, Hughes BA, Cassidy AM, Thompson E, 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. 2012;97:507–16.

    Article  CAS  PubMed  Google Scholar 

  116. •• 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. A critical study revealing the complexity of therapeutically resistant clones in CRPC associated with regional and temporal heterogeneity, which can be monitored by sequential plasma and tumor biopsies to target lethal disease.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Drake JM, Paull EO, Graham NA, Lee JK, Smith BA, Titz B, et al. Phosphoproteome integration reveals patient-specific networks in prostate cancer. Cell. 166:1041–54.

  118. •• Sweeney CJ, Chen Y-H, 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. Shows a significant overall survival benefit in the addition of docetaxel to first-line ADT in metastatic hormone-sensitive prostate cancer, supporting the importance of targeting androgen sensitive and not CRPC by taxane chemotherapy to overcome cross-resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. •• James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163–77. Shows a significant overall survival benefit in the addition of docetaxel to first-line ADT in metastatic hormone-sensitive prostate cancer, supporting the importance of targeting androgen sensitive and not CRPC by taxane chemotherapy to overcome cross-resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Petrylak DP, Tangen CM, Hussain MHA, Lara PNJ, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–20.

    Article  CAS  PubMed  Google Scholar 

  121. Pienta KJ. Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Seminars in Oncology; 2001: Elsevier; 2001. p. 3–7.

  122. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4:253–65.

    Article  CAS  PubMed  Google Scholar 

  123. Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, et al. Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res. 2011;71:6019–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. O’Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, Gallagher WM, et al. Characterisation and manipulation of docetaxel resistant prostate cancer cell lines. Mol Cancer. 2011;10:1–13.

    Article  CAS  Google Scholar 

  125. Terry S, Ploussard G, Allory Y, Nicolaiew N, Boissiere-Michot F, Maille P, et al. Increased expression of class III beta-tubulin in castration-resistant human prostate cancer. Br J Cancer. 2009;101:951–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ploussard G, Terry S, Maillé P, Allory Y, Sirab N, Kheuang L, et al. Class III β-tubulin expression predicts prostate tumor aggressiveness and patient response to docetaxel-based chemotherapy. Cancer Res. 2010;70:9253–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Martin SK, Kyprianou N. Chapter three—Exploitation of the androgen receptor to overcome taxane resistance in advanced prostate ancer. In: Paul BF, Kenneth DT, eds. Advances in cancer research. Academic; 2015. p. 123–58.

  128. 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. Annals of Oncology. 2015;26:1859–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Martin SK, Pu H, Penticuff JC, Cao Z, Horbinski C, Kyprianou N. Multinucleation and mesenchymal-to-epithelial transition alleviate resistance to combined cabazitaxel and antiandrogen therapy in advanced prostate cancer. Cancer Res. 2015.

  130. Martin SK, Banuelos CA, Sadar MD, Kyprianou N. N-terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy. Mol Oncol. 2015;9:628–39.

    Article  CAS  Google Scholar 

  131. Wyatt AW, Mo F, Wang Y, Collins CC. The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing. Asian Journal of Andrology. 2013;15:301–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discovery. 2016;6:479–91.

    Article  PubMed  CAS  Google Scholar 

  133. Small EJ, Lance RS, Gardner TA, Karsh LI, Fong L, McCoy C, et al. A randomized phase II trial of sipuleucel-T with concurrent versus sequential abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. American Association for Cancer Research. 2015;21:3862–9.

    CAS  Google Scholar 

  134. Paller CJ, Bradbury PA, Ivy SP, Seymour L, LoRusso PM, Baker L, et al. Design of phase I combination trials: recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee. Clinical Cancer Research. 2014;20:4210–7.

    Article  PubMed  PubMed Central  Google Scholar 

  135. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med.0:null.

  137. Cao Z, Kyprianou N. Mechanisms navigating the TGF-β pathway in prostate cancer. Asian Journal of Urology. 2015;2:11–8.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge the support of this work through funding from the James F. Hardymon Endowment in Urologic Research at the University of Kentucky (NK), NIH grant K23CA197526 (CP); the National Center for Advancing Translational Sciences, UL1TR000117 (MN); and the Dean of the College of Medicine at the University of Kentucky.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Natasha Kyprianou.

Ethics declarations

Conflict of Interest

Mary Nakazawa, Channing Paller, and Natasha Kyprianou declare that they have no conflict of interest.

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.

Additional information

This article is part of the Topical Collection on Genitourinary Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakazawa, M., Paller, C. & Kyprianou, N. Mechanisms of Therapeutic Resistance in Prostate Cancer. Curr Oncol Rep 19, 13 (2017). https://doi.org/10.1007/s11912-017-0568-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-017-0568-7

Keywords

Navigation