
Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects
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ABSTRACT Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally
advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several
years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence
showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms
of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. Access through your institution Buy or
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SECOND GENERATION ANDROGEN RECEPTOR ANTAGONISTS AND CHALLENGES IN PROSTATE CANCER TREATMENT Article Open access 21 July 2022 LOSS AND REVIVAL OF ANDROGEN RECEPTOR SIGNALING IN ADVANCED
PROSTATE CANCER Article Open access 08 January 2021 RESISTANCE TO SECOND-GENERATION ANDROGEN RECEPTOR ANTAGONISTS IN PROSTATE CANCER Article 19 March 2021 REFERENCES * Huggins C, Hodges CV .
Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. _Cancer Res_ 1941; 1: 293–297.
CAS Google Scholar * 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. CAS PubMed PubMed Central Google Scholar * 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: 138–148. CAS PubMed Google Scholar * 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: 1187–1197. CAS PubMed Google Scholar * Garraway LA, Sellers WR . Lineage dependency and lineage-survival
oncogenes in human cancer. _Nat Rev Cancer_ 2006; 6: 593–602. CAS PubMed Google Scholar * Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO .
Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. _Mol Endocrinol_ 1991; 5: 1396–1404. CAS PubMed Google Scholar
* Heinlein CA, Chang C . Androgen receptor (AR) coregulators: an overview. _Endocr Rev_ 2002; 23: 175–200. CAS PubMed Google Scholar * Georget V, Terouanne B, Nicolas JC, Sultan C .
Mechanism of antiandrogen action: key role of hsp90 in conformational change and transcriptional activity of the androgen receptor. _Biochemistry_ 2002; 41: 11824–11831. CAS PubMed Google
Scholar * Prescott J, Coetzee GA . Molecular chaperones throughout the life cycle of the androgen receptor. _Cancer Lett_ 2006; 231: 12–19. CAS PubMed Google Scholar * van de Wijngaart
DJ, Dubbink HJ, van Royen ME, Trapman J, Jenster G . Androgen receptor coregulators: recruitment via the coactivator binding groove. _Mol Cell Endocrinol_ 2012; 352: 57–69. CAS PubMed
Google Scholar * Askew EB, Minges JT, Hnat AT, Wilson EM . Structural features discriminate androgen receptor N/C terminal and coactivator interactions. _Mol Cell Endocrinol_ 2012; 348:
403–410. CAS PubMed Google Scholar * Schaufele F, Carbonell X, Guerbadot M, Borngraeber S, Chapman MS, Ma AA _et al_. The structural basis of androgen receptor activation: intramolecular
and intermolecular amino-carboxy interactions. _Proc Natl Acad Sci USA_ 2005; 102: 9802–9807. CAS PubMed PubMed Central Google Scholar * van Royen ME, Cunha SM, Brink MC, Mattern KA,
Nigg AL, Dubbink HJ _et al_. Compartmentalization of androgen receptor protein-protein interactions in living cells. _J Cell Biol_ 2007; 177: 63–72. CAS PubMed PubMed Central Google
Scholar * He B, Kemppainen JA, Wilson EM . FXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor. _J Biol Chem_ 2000; 275:
22986–22994. CAS PubMed Google Scholar * Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE . Structural basis for the nuclear import of the human androgen receptor. _J Cell Sci_ 2008;
121: 957–968. CAS PubMed Google Scholar * Zoubeidi A, Zardan A, Beraldi E, Fazli L, Sowery R, Rennie P _et al_. Cooperative interactions between androgen receptor (AR) and heat-shock
protein 27 facilitate AR transcriptional activity. _Cancer Res_ 2007; 67: 10455–10465. CAS PubMed Google Scholar * Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW _et
al_. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. _Science_ 2005; 310: 644–648. CAS PubMed Google Scholar * Palanisamy N, Ateeq B, Kalyana-Sundaram
S, Pflueger D, Ramnarayanan K, Shankar S _et al_. Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. _Nat Med_ 2010; 16: 793–798. CAS PubMed PubMed
Central Google Scholar * Attard G, de Bono JS, Clark J, Cooper CS . Studies of TMPRSS2-ERG gene fusions in diagnostic trans-rectal prostate biopsies. _Clin Cancer Res_ 2010; 16: 1340;
author reply 1340. CAS PubMed PubMed Central Google Scholar * Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'Hern R _et al_. Characterization of ERG, AR and PTEN gene
status in circulating tumor cells from patients with castration-resistant prostate cancer. _Cancer Res_ 2009; 69: 2912–2918. CAS PubMed Google Scholar * Lu S, Jenster G, Epner DE .
Androgen induction of cyclin-dependent kinase inhibitor p21 gene: role of androgen receptor and transcription factor Sp1 complex. _Mol Endocrinol_ 2000; 14: 753–760. CAS PubMed Google
Scholar * Cinar B, Mukhopadhyay NK, Meng G, Freeman MR . Phosphoinositide 3-kinase-independent non-genomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains.
_J Biol Chem_ 2007; 282: 29584–29593. CAS PubMed Google Scholar * Castoria G, Lombardi M, Barone MV, Bilancio A, Di Domenico M, De Falco A _et al_. Rapid signalling pathway activation by
androgens in epithelial and stromal cells. _Steroids_ 2004; 69: 517–522. CAS PubMed Google Scholar * Unni E, Sun S, Nan B, McPhaul MJ, Cheskis B, Mancini MA _et al_. Changes in androgen
receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. _Cancer Res_ 2004; 64: 7156–7168. CAS PubMed Google Scholar * Mostaghel EA, Page ST,
Lin DW, Fazli L, Coleman IM, True LD _et al_. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for
castration-resistant prostate cancer. _Cancer Res_ 2007; 67: 5033–5041. CAS PubMed Google Scholar * Geller J, Albert J, Loza D, Geller S, Stoeltzing W, de la Vega D . DHT concentrations
in human prostate cancer tissue. _J Clin Endocrinol Metab_ 1978; 46: 440–444. CAS PubMed Google Scholar * 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: 4447–4454. CAS PubMed PubMed Central Google
Scholar * Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL . Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. _Clin Cancer Res_ 2005; 11: 4653–4657. CAS
PubMed Google Scholar * 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: 6407–6415. CAS PubMed Google Scholar * 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: 2815–2825. CAS PubMed Google Scholar * Mitsiades N, Sung
CC, Schultz N, Danila DC, He B, Eedunuri VK _et al_. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer
tumors. _Cancer Res_ 2012; 72: 6142–6152. CAS PubMed PubMed Central Google Scholar * Russell DW, Wilson JD . Steroid 5 alpha-reductase: two genes/two enzymes. _Annu Rev Biochem_ 1994;
63: 25–61. CAS PubMed Google Scholar * Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y _et al_. Novel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpressed in
hormone-refractory prostate cancer. _Cancer Sci_ 2008; 99: 81–86. CAS PubMed Google Scholar * Godoy A, Kawinski E, Li Y, Oka D, Alexiev B, Azzouni F _et al_. 5alpha-reductase type 3
expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression. _Prostate_ 2011; 71: 1033–1046. CAS PubMed Google Scholar * 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: 1074–1084. CAS PubMed PubMed Central
Google Scholar * Brooke GN, Bevan CL . The role of androgen receptor mutations in prostate cancer progression. _Curr Genomics_ 2009; 10: 18–25. CAS PubMed PubMed Central Google Scholar
* Bergerat JP, Ceraline J . Pleiotropic functional properties of androgen receptor mutants in prostate cancer. _Hum Mutat_ 2009; 30: 145–157. CAS PubMed Google Scholar * 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: 1393–1398. CAS
PubMed Google Scholar * Taplin ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J _et al_. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia
Group B Study 9663. _J Clin Oncol_ 2003; 21: 2673–2678. Article CAS PubMed Google Scholar * Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr C _et al_. Mutant androgen
receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. _Mol Endocrinol_ 1993; 7: 1541–1550. CAS PubMed Google Scholar * Wallen MJ,
Linja M, Kaartinen K, Schleutker J, Visakorpi T . Androgen receptor gene mutations in hormone-refractory prostate cancer. _J Pathol_ 1999; 189: 559–563. CAS PubMed Google Scholar * Taplin
ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B _et al_. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. _Cancer Res_ 1999; 59:
2511–2515. CAS PubMed Google Scholar * Steinkamp MP, O'Mahony OA, Brogley M, Rehman H, Lapensee EW, Dhanasekaran S _et al_. Treatment-dependent androgen receptor mutations in
prostate cancer exploit multiple mechanisms to evade therapy. _Cancer Res_ 2009; 69: 4434–4442. CAS PubMed PubMed Central Google Scholar * Scher HI, Kelly WK . Flutamide withdrawal
syndrome: its impact on clinical trials in hormone-refractory prostate cancer. _J Clin Oncol_ 1993; 11: 1566–1572. CAS PubMed Google Scholar * 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: 149–153. CAS PubMed Google Scholar *
Okegawa T, Nutahara K, Higashihara E . Alternative antiandrogen therapy in patients with castration-resistant prostate cancer: a single-center experience. _Int J Urol_ 2010; 17: 950–955.
PubMed Google Scholar * Choi JI, Kim YB, Yang SO, Lee JK, Jung TY . Efficacy of alternative antiandrogen therapy for prostate cancer that relapsed after initial maximum androgen blockade.
_Korean J Urol_ 2011; 52: 461–465. PubMed PubMed Central Google Scholar * 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: 1030–1043. CAS PubMed Google Scholar * 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. PubMed PubMed Central Google Scholar * 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: 1020–1029. CAS PubMed Google Scholar * 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: 803–806. CAS PubMed Google Scholar * Haapala K, Kuukasjarvi T, Hyytinen E, Rantala
I, Helin HJ, Koivisto PA . Androgen receptor amplification is associated with increased cell proliferation in prostate cancer. _Hum Pathol_ 2007; 38: 474–478. CAS PubMed Google Scholar *
Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T . Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. _Cancer Res_
2001; 61: 3550–3555. CAS PubMed Google Scholar * 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. CAS PubMed PubMed Central Google Scholar * 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: 314–319. CAS PubMed Google Scholar * 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: 401–406. CAS PubMed Google
Scholar * Miyoshi Y, Uemura H, Fujinami K, Mikata K, Harada M, Kitamura H _et al_. Fluorescence _in situ_ hybridization evaluation of c-myc and androgen receptor gene amplification and
chromosomal anomalies in prostate cancer in Japanese patients. _Prostate_ 2000; 43: 225–232. CAS PubMed Google Scholar * Leversha MA, Han J, Asgari Z, Danila DC, Lin O, Gonzalez-Espinoza
R _et al_. Fluorescence _in situ_ hybridization analysis of circulating tumor cells in metastatic prostate cancer. _Clin Cancer Res_ 2009; 15: 2091–2097. CAS PubMed PubMed Central Google
Scholar * 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: 489–499. CAS
PubMed PubMed Central Google Scholar * Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C _et al_. The retinoblastoma tumor suppressor controls androgen signaling and human
prostate cancer progression. _J Clin Invest_ 2010; 120: 4478–4492. CAS PubMed PubMed Central Google Scholar * Lin PC, Chiu YL, Banerjee S, Park K, Mosquera JM, Giannopoulou E _et al_.
Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression. _Cancer Res_ 2013; 73: 1232–1244. CAS PubMed Google Scholar * Wiren
KM, Zhang X, Chang C, Keenan E, Orwoll ES . Transcriptional up-regulation of the human androgen receptor by androgen in bone cells. _Endocrinology_ 1997; 138: 2291–2300. CAS PubMed Google
Scholar * Wolf DA, Herzinger T, Hermeking H, Blaschke D, Horz W . Transcriptional and posttranscriptional regulation of human androgen receptor expression by androgen. _Mol Endocrinol_
1993; 7: 924–936. CAS PubMed Google Scholar * Grad JM, Dai JL, Wu S, Burnstein KL . Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding
region are involved in androgen-mediated up-regulation of AR messenger RNA. _Mol Endocrinol_ 1999; 13: 1896–1911. CAS PubMed Google Scholar * Grad JM, Lyons LS, Robins DM, Burnstein KL .
The androgen receptor (AR) amino-terminus imposes androgen-specific regulation of AR gene expression via an exonic enhancer. _Endocrinology_ 2001; 142: 1107–1116. CAS PubMed Google Scholar
* Waltering KK, Helenius MA, Sahu B, Manni V, Linja MJ, Janne OA _et al_. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. _Cancer
Res_ 2009; 69: 8141–8149. CAS PubMed Google Scholar * 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: 33–39. PubMed Google Scholar * 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. CAS PubMed PubMed Central Google Scholar * Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall
DJ . Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. _Cancer Res_ 2008; 68: 5469–5477. CAS
PubMed PubMed Central Google Scholar * 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: 2305–2313. CAS PubMed PubMed Central Google Scholar * 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: 2715–2730. CAS
PubMed PubMed Central Google Scholar * Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale 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_ 2010; 107: 16759–16765. CAS PubMed PubMed Central Google Scholar * Li Y, Alsagabi M,
Fan D, Bova GS, Tewfik AH, Dehm SM . Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. _Cancer Res_ 2011; 71:
2108–2117. CAS PubMed PubMed Central Google Scholar * Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X . Mechanisms of the androgen receptor splicing in prostate cancer cells.
_Oncogene_ (e-pub ahead of print 15 July 2013; doi: 10.1038/onc.2013.284). PubMed PubMed Central Google Scholar * Luo J, Pienta KJ . Words of wisdom: re: androgen receptor splice variants
mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. _Eur Urol_ 2013; 64: 339–340. CAS PubMed Google Scholar * Plymate SR Luo J . The expression signature
of androgen receptor splice variants and their distinctive transcriptional activities in castration-resistant prostate cancer. In: Zhou W (ed). _Androgen-Responsive Genes in Prostate
Cancer_. Springer: New York, NY, USA, 2013. Google Scholar * 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: 3457–3462. CAS PubMed PubMed Central Google Scholar
* 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: 483–489. CAS PubMed Google Scholar * 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. _Clin Cancer Res_ 2011; 17: 5913–5925. CAS PubMed PubMed Central Google Scholar
* Verras M, Lee J, Xue H, Li TH, Wang Y, Sun Z . The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression.
_Cancer Res_ 2007; 67: 967–975. CAS PubMed Google Scholar * Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S _et al_. Reciprocal feedback regulation of PI3K and
androgen receptor signaling in PTEN-deficient prostate cancer. _Cancer Cell_ 2011; 19: 575–586. CAS PubMed PubMed Central Google Scholar * Wu JD, Haugk K, Woodke L, Nelson P, Coleman I,
Plymate SR . Interaction of IGF signaling and the androgen receptor in prostate cancer progression. _J Cell Biochem_ 2006; 99: 392–401. CAS PubMed Google Scholar * Signoretti S, Montironi
R, Manola J, Altimari A, Tam C, Bubley G _et al_. Her-2-neu expression and progression toward androgen independence in human prostate cancer. _J Natl Cancer Inst_ 2000; 92: 1918–1925. CAS
PubMed Google Scholar * Di Lorenzo G, Tortora G, D'Armiento FP, De Rosa G, Staibano S, Autorino R _et al_. Expression of epidermal growth factor receptor correlates with disease
relapse and progression to androgen-independence in human prostate cancer. _Clin Cancer Res_ 2002; 8: 3438–3444. CAS PubMed Google Scholar * Reid AH, Attard G, Ambroisine L, Fisher G,
Kovacs G, Brewer D _et al_. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. _Br J Cancer_ 2010; 102:
678–684. CAS PubMed PubMed Central Google Scholar * Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP _et al_. The mutational landscape of lethal castration-resistant
prostate cancer. _Nature_ 2012; 487: 239–243. CAS PubMed PubMed Central Google Scholar * Robbins CM, Tembe WA, Baker A, Sinari S, Moses TY, Beckstrom-Sternberg S _et al_. Copy number and
targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. _Genome Res_ 2011; 21: 47–55. CAS PubMed PubMed Central Google Scholar * Berger MF, Lawrence MS,
Demichelis F, Drier Y, Cibulskis K, Sivachenko AY _et al_. The genomic complexity of primary human prostate cancer. _Nature_ 2011; 470: 214–220. CAS PubMed PubMed Central Google Scholar
* Thomas C, Lamoureux F, Crafter C, Davies BR, Beraldi E, Fazli L _et al_. Synergistic targeting of PI3K/AKT pathway and androgen receptor axis significantly delays castration-resistant
prostate cancer progression _in vivo_. _Mol Cancer Ther_ 2013; 12: 2342–2355. CAS PubMed Google Scholar * Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM . Androgen receptor
coregulators and their involvement in the development and progression of prostate cancer. _Int J Cancer_ 2007; 120: 719–733. CAS PubMed Google Scholar * Jozwik KM, Carroll JS . Pioneer
factors in hormone-dependent cancers. _Nat Rev Cancer_ 2012; 12: 381–385. CAS PubMed Google Scholar * Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP _et al_.
Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. _Nat Genet_ 2012; 44: 685–689. CAS PubMed PubMed Central Google Scholar * Geng C, He B, Xu L,
Barbieri CE, Eedunuri VK, Chew SA _et al_. Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. _Proc Natl Acad
Sci USA_ 2013; 110: 6997–7002. CAS PubMed PubMed Central Google Scholar * Coffey K, Robson CN . Regulation of the androgen receptor by post-translational modifications. _J Endocrinol_
2012; 215: 221–237. CAS PubMed Google Scholar * Lamont KR, Tindall DJ . Minireview: Alternative activation pathways for the androgen receptor in prostate cancer. _Mol Endocrinol_ 2011;
25: 897–907. CAS PubMed PubMed Central Google Scholar * Shu SK, Liu Q, Coppola D, Cheng JQ . Phosphorylation and activation of androgen receptor by Aurora-A. _J Biol Chem_ 2010; 285:
33045–33053. CAS PubMed PubMed Central Google Scholar * Chen S, Xu Y, Yuan X, Bubley GJ, Balk SP . Androgen receptor phosphorylation and stabilization in prostate cancer by
cyclin-dependent kinase 1. _Proc Natl Acad Sci USA_ 2006; 103: 15969–15974. CAS PubMed PubMed Central Google Scholar * Willder JM, Heng SJ, McCall P, Adams CE, Tannahill C, Fyffe G _et
al_. Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients. _Br J Cancer_ 2013; 108: 139–148. CAS PubMed Google Scholar * Ha S,
Iqbal NJ, Mita P, Ruoff R, Gerald WL, Lepor H _et al_. Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer. _Oncogene_ 2012; 32: 3992–4000. PubMed PubMed
Central Google Scholar * Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O _et al_. Regulation of androgen receptor activity by tyrosine phosphorylation. _Cancer Cell_ 2006; 10: 309–319. CAS
PubMed Google Scholar * Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL _et al_. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen
receptor tyrosine phosphorylation. _Proc Natl Acad Sci USA_ 2007; 104: 8438–8443. CAS PubMed PubMed Central Google Scholar * Liu Y, Karaca M, Zhang Z, Gioeli D, Earp HS, Whang YE .
Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. _Oncogene_ 2010; 29: 3208–3216. CAS PubMed PubMed Central Google Scholar * Fong
PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M _et al_. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. _N Engl J Med_ 2009; 361: 123–134. CAS PubMed
Google Scholar * Yap TA, Sandhu SK, Carden CP, de Bono JS . Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic. _CA Cancer J Clin_ 2011;
61: 31–49. PubMed Google Scholar * Sandhu SK, Omlin A, Hylands L, Miranda S, Barber LJ, Riisnaes R _et al_. Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced
germline BRCA2 mutant prostate cancer. _Ann Oncol_ 2013; 24: 1416–1418. CAS PubMed Google Scholar * Kraus WL . Transcriptional control by PARP-1: chromatin modulation, enhancer-binding,
coregulation, and insulation. _Curr Opin Cell Biol_ 2008; 20: 294–302. CAS PubMed PubMed Central Google Scholar * Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL _et al_.
Dual roles of PARP-1 promote cancer growth and progression. _Cancer Discov_ 2012; 2: 1134–1149. CAS PubMed PubMed Central Google Scholar * Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q,
Asangani IA _et al_. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. _Cancer Cell_ 2011; 19: 664–678. CAS PubMed PubMed
Central Google Scholar * Beltran H . DNA mismatch repair in prostate cancer. _J Clin Oncol_ 2013; 31: 1782–1784. CAS PubMed Google Scholar * Montgomery B, Cheng HH, Drechsler J,
Mostaghel EA . Glucocorticoids and prostate cancer treatment: friend or foe? _Asian J Androl_ (e-pub ahead of print 7 March 2014; doi: 10.4103/1008-682X.125392). PubMed PubMed Central
Google Scholar * Szmulewitz RZ, Chung E, Al-Ahmadie H, Daniel S, Kocherginsky M, Razmaria A _et al_. Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers.
_Prostate_ 2012; 72: 157–164. CAS PubMed Google Scholar * Sahu B, Laakso M, Pihlajamaa P, Ovaska K, Sinielnikov I, Hautaniemi S _et al_. FoxA1 specifies unique androgen and glucocorticoid
receptor binding events in prostate cancer cells. _Cancer Res_ 2013; 73: 1570–1580. CAS PubMed Google Scholar * 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: 1309–1322. CAS PubMed PubMed Central Google Scholar *
Brinkmann AO, Faber PW, van Rooij HC, Kuiper GG, Ris C, Klaassen P _et al_. The human androgen receptor: domain structure, genomic organization and regulation of expression. _J Steroid
Biochem_ 1989; 34: 307–310. CAS PubMed Google Scholar * Laudet V, Hanni C, Coll J, Catzeflis F, Stehelin D . Evolution of the nuclear receptor gene superfamily. _EMBO J_ 1992; 11:
1003–1013. CAS PubMed PubMed Central Google Scholar * Barrie SE, Potter GA, Goddard PM, Haynes BP, Dowsett M, Jarman M . Pharmacology of novel steroidal inhibitors of cytochrome P450(17)
alpha (17 alpha-hydroxylase/C17-20 lyase). _J Steroid Biochem Mol Biol_ 1994; 50: 267–273. CAS PubMed Google Scholar * Barrie SE, Haynes BP, Potter GA, Chan FC, Goddard PM, Dowsett M _et
al_. Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P450(17alpha) inhibitors. _J Steroid Biochem Mol Biol_ 1997; 60: 347–351. CAS PubMed Google Scholar * Potter GA,
Barrie SE, Jarman M, Rowlands MG . Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer.
_J Med Chem_ 1995; 38: 2463–2471. CAS PubMed Google Scholar * O'Donnell AI, Judson I, Dowsett M, Dowsett M, Raynaud F, Dearnaley D _et al_. Hormonal impact of the
17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. _Br J Cancer_ 2004; 90: 2317–2325. CAS PubMed PubMed Central Google Scholar *
Ferraldeschi R, de Bono J . Agents that target androgen synthesis in castration-resistant prostate cancer. _Cancer J_ 2013; 19: 34–42. CAS PubMed Google Scholar * 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. _J Clin Oncol_ 2008; 26: 4563–4571. CAS PubMed Google Scholar * 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: 983–992. CAS PubMed Google Scholar * Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN _et al_. Effect of abiraterone acetate and prednisone compared with placebo and
prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.
_Lancet Oncol_ 2012; 13: 1210–1217. CAS PubMed Google Scholar * Kaku T, Hitaka T, Ojida A, Matsunaga N, Adachi M, Tanaka T _et al_. Discovery of orteronel (TAK-700), a
naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. _Bioorg Med Chem_ 2011; 19: 6383–6399. CAS PubMed
Google Scholar * Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P _et al_. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, _in vitro_
biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. _J Med Chem_ 2005; 48: 2972–2984. CAS PubMed Google Scholar * Eisner JR,
Abbott DH, Bird IM, Rafferty SW, Moore MR, Schotzinger RJ . VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate cancer (CRPC). _J Clin
Oncol_ 2012; 30: (abstr e15167). Google Scholar * Kikuchi A, Enjo K, Furutani T, Azami H, Nimi T, Kuromitsu S _et al_. ASP9521, a novel, selective, orally bioavailable AKR1C3 (type 5,
17ß-hydroxysteroid dehydrogenase) inhibitor: _In vitro_ and _in vivo_ characterization. _J Clin Oncol 31_ 2013 (suppl; abstr 5046). * Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A,
Pezaro C _et al_. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). _Ann Oncol_
2013; 24: 1807–1812. CAS PubMed Google Scholar * 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 USA_ 2005; 102: 6201–6206. CAS PubMed PubMed Central Google Scholar * Jarman M, Barrie SE, Llera JM . The 16,17-double bond is needed for irreversible inhibition of human
cytochrome p45017alpha by abiraterone (17-(3-pyridyl)androsta-5, 16-dien-3beta-ol) and related steroidal inhibitors. _J Med Chem_ 1998; 41: 5375–5381. CAS PubMed Google Scholar *
Osguthorpe DJ, Hagler AT . Mechanism of androgen receptor antagonism by bicalutamide in the treatment of prostate cancer. _Biochemistry_ 2011; 50: 4105–4113. CAS PubMed Google Scholar *
Kolvenbag GJ, Furr BJ, Blackledge GR . Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity. _Prostate Cancer Prostatic
Dis_ 1998; 1: 307–314. CAS PubMed Google Scholar * Simard J, Singh SM, Labrie F . Comparison of _in vitro_ effects of the pure antiandrogens OH-flutamide, Casodex, and nilutamide on
androgen-sensitive parameters. _Urology_ 1997; 49: 580–586; discussion 586-589. CAS PubMed Google Scholar * Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C _et al_. Structure-activity
relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). _J Med Chem_ 2010; 53: 2779–2796. CAS PubMed PubMed Central Google Scholar *
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:
1437–1446. CAS PubMed PubMed Central Google Scholar * Beer TM, Sternberg CN, Higano CS, Iversen P, Loriot Y, Rathkopf DE _et al_. Enzalutamide in men with chemotherapy-naive metastatic
prostate cancer (mCRPC): Results of phase III PREVAIL study. _J Clin Oncol_ 2014; 32 (suppl 4; abstr LBA1). Google Scholar * Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A _et
al_. ARN-509: a novel antiandrogen for prostate cancer treatment. _Cancer Res_ 2012; 72: 1494–1503. CAS PubMed PubMed Central Google Scholar * Rathkopf DE, Morris MJ, Fox JJ, Danila DC,
Slovin SF, Hager JH _et al_. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. _J Clin Oncol_ 2013; 31: 3525–3530. CAS PubMed PubMed
Central Google Scholar * Smith MR, Antonarakis ES, Ryan CJ, Berry W, Shore ND, Liu G _et al_. Arn-509 in Men with High Risk Non-Metastatic Castration-Resistant Prostate Cancer. _Ann
Oncol_ 2012; 23: 303–303. Google Scholar * Fizazi K, Massard C, James ND, Culine S, Jones RH, Oksala R _et al_. ODM-201, a new generation androgen receptor inhibitor for
castration-resistant prostate cancer: preclinical and phase I data. _J Clin Oncol_ 2013; 31 (Suppl 6; abstr 65). Google Scholar * Massard C, James N, Culine S, Jones R, Vuorela A, Mustonen
M _et al_. ARADES trial: A first-in-man, open-label, phase I/II safety, pharmacokinetic, and proof-of-concept study ofODM-201 in patients (pts) with progressive metastatic
castration-resistant prostate cancer (mCRPC). Presented at the 2012 ESMO Congress; Vienna, Austria Abstract LBA25_PR (2012). * Lavery DN, McEwan J Functional characterization of the native
NH2-terminal transactivation domain of the human androgen receptor: binding kinetics for interactions with TFIIF and SRC-1a. _Biochemistry_ 2008; 47: 3352–3359. CAS PubMed Google Scholar
* Lavery DN, McEwan IJ . Structural characterization of the native NH2-terminal transactivation domain of the human androgen receptor: a collapsed disordered conformation underlies
structural plasticity and protein-induced folding. _Biochemistry_ 2008; 47: 3360–3369. CAS PubMed Google Scholar * Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK _et al_.
Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. _Cancer Cell_ 2010; 17: 535–546. CAS PubMed Google
Scholar * Zhang Y, Castaneda S, Dumble M, Wang M, Mileski M, Qu Z _et al_. Reduced expression of the androgen receptor by third generation of antisense shows antitumor activity in models of
prostate cancer. _Mol Cancer Ther_ 2011; 10: 2309–2319. CAS PubMed Google Scholar * Bianchini D, Omlin A, Pezaro C, Lorente D, Ferraldeschi R, Mukherji D _et al_. First-in-human Phase I
study of EZN-4176, a locked nucleic acid antisense oligonucleotide to exon 4 of the androgen receptor mRNA in patients with castration-resistant prostate cancer. _Br J Cancer_ 2013; 109:
2579–2586. CAS PubMed PubMed Central Google Scholar * Ravindranathan P, Lee TK, Yang L, Centenera MM, Butler L, Tilley WD _et al_. Peptidomimetic targeting of critical androgen
receptor-coregulator interactions in prostate cancer. _Nat Commun_ 2013; 4: 1923. PubMed Google Scholar * Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A _et al_. A
phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. _Clin Cancer Res_ 2011; 17: 1561–1570. CAS PubMed
PubMed Central Google Scholar * Heath EI, Stein MN, Vaishampayan UN, Antonarakis ES, Liu G, Sheng S _et al_. Phase II trial of single-agent ganetespib (STA-9090), a heat shock protein 90
(Hsp90) inhibitor in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) post docetaxel-based chemotherapy: Results of a Prostate Cancer Clinical Trials
Consortium (PCCTC) study. _J Clin Oncol_ 2013; 31 (suppl, abstr 5085). * Gibbs A, Schwartzman J, Deng V, Alumkal J . Sulforaphane destabilizes the androgen receptor in prostate cancer cells
by inactivating histone deacetylase 6. _Proc Natl Acad Sci USA_ 2009; 106: 16663–16668. CAS PubMed PubMed Central Google Scholar * Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD,
Miranda S _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_
2013; 14: 882–892. CAS PubMed Google Scholar * Jiang X, Chen S, Asara JM, Balk SP . Phosphoinositide 3-kinase pathway activation in phosphate and tensin homolog (PTEN)-deficient prostate
cancer cells is independent of receptor tyrosine kinases and mediated by the p110beta and p110delta catalytic subunits. _J Biol Chem_ 2010; 285: 14980–14989. CAS PubMed PubMed Central
Google Scholar * Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K _et al_. Functional characterization of an isoform-selective inhibitor of PI3K-p110beta as a potential anticancer agent.
_Cancer Discov_ 2012; 2: 425–433. CAS PubMed PubMed Central Google Scholar * Zhu Q, Youn H, Tang J, Tawfik O, Dennis K, Terranova PF _et al_. Phosphoinositide 3-OH kinase p85alpha and
p110beta are essential for androgen receptor transactivation and tumor progression in prostate cancers. _Oncogene_ 2008; 27: 4569–4579. CAS PubMed PubMed Central Google Scholar *
Cariaga-Martinez AE, Lopez-Ruiz P, Nombela-Blanco MP, Motino O, Gonzalez-Corpas A, Rodriguez-Ubreva J _et al_. Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and
androgen-independent prostate cancer cells. _Cell Signal_ 2013; 25: 1586–1597. CAS PubMed Google Scholar * Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ _et al_.
Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. _Cancer Res_ 2008; 68: 2366–2374. CAS PubMed Google Scholar * Smith DC, Smith MR, Sweeney
C, Elfiky AA, Logothetis C, Corn PG _et al_. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. _J Clin Oncol_ 2013; 31: 412–419.
CAS PubMed Google Scholar * Michaelson MD, Oudard S, Ou YC, Sengelov L, Saad F, Houede N _et al_. Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus
Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer. _J Clin Oncol_ 2014; 32: 76–82. CAS PubMed Google Scholar * Araujo JC, Trudel GC, Saad F, Armstrong AJ,
Yu EY, Bellmunt J _et al_. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. _Lancet Oncol_
2013; 14: 1307–1316. CAS PubMed PubMed Central Google Scholar * Yu EY, Wilding G, Posadas E, Gross M, Culine S, Massard C _et al_. Phase II study of dasatinib in patients with metastatic
castration-resistant prostate cancer. _Clin Cancer Res_ 2009; 15: 7421–7428. CAS PubMed PubMed Central Google Scholar * Sonpavde G, Periman PO, Bernold D, Weckstein D, Fleming MT,
Galsky MD _et al_. Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. _Ann Oncol_ 2010; 21: 319–324. CAS PubMed Google Scholar *
Taplin ME, Montgomery RB, Logothetis C, Bubley GJ, Richie JP, Dalkin BL _et al_. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete
response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. _J Clin Oncol_ 2012; 30 (suppl; abstr 4521). * Tombal B, Borre M,
Rathenborg P, Werbrouck P, Poppel HV, Heidenreich A _et al_. Enzalutamide monotherapy: Extended follow-up of a phase II study in hormone-naive prostate cancer patients. _J Clin Oncol_ 2014;
32 (suppl 4; abstr 62). Google Scholar * Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA _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_ 2011; 71: 6503–6513. CAS PubMed PubMed Central Google Scholar * Yu Z, Chen S,
Sowalsky AG, Voznesensky O, Mostaghel EA, Nelson PS _et al_. Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate Cancer. _Clin Cancer Res_ 2014; 20:
1590–1600. CAS PubMed PubMed Central Google Scholar * Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K _et al_. Interactions of abiraterone, eplerenone, and prednisolone
with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. _Cancer Res_ 2012; 72: 2176–2182. CAS PubMed PubMed Central Google
Scholar * Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E _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_ 1990; 173: 534–540. CAS PubMed Google Scholar * 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: 703–706. CAS PubMed
Google Scholar * Bianchini D, Lorente D, Rodriguez-Vida A, Omlin A, Pezaro C, Ferraldeschi R _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_ 2014; 50: 78–84. CAS PubMed Google Scholar * Schrader AJ, Boegemann M, Ohlmann CH,
Schnoeller TJ, Krabbe LM, Hajili T _et al_. Enzalutamide in Castration-resistant Prostate Cancer Patients Progressing After Docetaxel and Abiraterone. _Eur Urol_ 2013; 65: 30–36. PubMed
Google Scholar * Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN . Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer
progressing after enzalutamide. _Ann Oncol_ 2013; 24: 1802–1807. CAS PubMed Google Scholar * Mosquera JM1, 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. CAS PubMed PubMed Central Google Scholar
Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Prostate Cancer Targeted Therapy Group, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey, UK,
R Ferraldeschi, J Welti, G Attard & J S de Bono * Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA J Luo Authors * R Ferraldeschi View author
publications You can also search for this author inPubMed Google Scholar * J Welti View author publications You can also search for this author inPubMed Google Scholar * J Luo View author
publications You can also search for this author inPubMed Google Scholar * G Attard View author publications You can also search for this author inPubMed Google Scholar * J S de Bono View
author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to J S de Bono. ETHICS DECLARATIONS COMPETING INTERESTS Abiraterone
acetate was developed at The Institute of Cancer Research (ICR), which therefore has a commercial interest in the development of this agent. JSdB received consulting fees from Ortho Biotech
Oncology Research and Development (a unit of Cougar Biotechnology), consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen and Takeda, and grant support from AstraZeneca and Genentech. GA
received consulting fees and travel support from Janssen-Cilag, Veridex, Roche/Ventana and Millennium Pharmaceuticals, lecture fees from Janssen-Cilag, Ipsen, Takeda and Sanofi-Aventis and
grant support from AstraZeneca and Genentech. GA is on the ICR rewards to inventors list of abiraterone acetate. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS
ARTICLE Ferraldeschi, R., Welti, J., Luo, J. _et al._ Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. _Oncogene_ 34, 1745–1757
(2015). https://doi.org/10.1038/onc.2014.115 Download citation * Received: 19 December 2013 * Revised: 24 March 2014 * Accepted: 24 March 2014 * Published: 19 May 2014 * Issue Date: 02 April
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