Molecular mechanisms of enzalutamide resistance in prostate cancer

Abstract

An estimated 30,000 men in the United States will die of metastatic prostate cancer (PCa) each year due to the development of therapy resistance, most notably resistance to second-generation antiandrogen enzalutamide. The vast majority of PCa is driven by the androgen receptor (AR). Enzalutamide is an AR antagonist, which extends patient survival and is widely used in the clinic for the treatment of castration-resistant prostate cancer (CRPC); however, many patients will have primary or develop acquired resistance and continue to progress. Characterization of the molecular mechanisms of enzalutamide resistance provides insight into potentially efficacious therapies for enzalutamide-resistant CRPC (ER-CRPC). Understanding these mechanisms is critical for the identification of biomarkers predictive of therapy resistance and the development of therapeutic strategies to target ER-CRPC.

Keywords

Drug resistant cancers / resistance modulation / biomarkers of drug responsiveness / targeted therapy resistance

References

[1] American Cancer Society. Cancer Facts & Figures 2018. Available from: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html. [Last accessed on 14 May 2019]

[2] Siegel RL,Jemal A.Cancer statistics, 2018..CA Cancer J Clin2018;68:7-30

[3] Antonarakis ES,Garrett-Mayer E.Survival in men with nonmetastatic prostate cancer treated with hormone therapy: a quantitative systematic review..J Clin Oncol2007;25:4998-5008 PMCID:PMC4133788

[4] Armstrong AJ,de Wit R,Eisenberger M.Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer..Clin Cancer Res2010;16:203-11

[5] Chen CD,Tran C,Chen R.Molecular determinants of resistance to antiandrogen therapy..Nat Med2004;10:33-9

[6] Loriot Y,de Bono JS,Hirmand M.Enzalutamide in castration-resistant prostate cancer patients with visceral disease in the liver and/or lung: outcomes from the randomized controlled phase 3 AFFIRM trial..Cancer2017;123:253-62 PMCID:PMC5632943

[7] Azad AA,Wyatt AW,Le Bihan S.Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer..Clin Cancer Res2015;21:2315-24

[8] Aparicio A,Maity SN.Understanding the lethal variant of prostate cancer: power of examining extremes..Cancer Discov2011;1:466-8 PMCID:PMC4133693

[9] Alanee S,Nutt M,Dynda D.Contemporary incidence and mortality rates of neuroendocrine prostate cancer..Anticancer Res2015;35:4145-50

[10] Robinson D,Wu YM,Lonigro RJ.Integrative clinical genomics of advanced prostate cancer..Cell2015;161:1215-28 PMCID:PMC4484602

[11] Beltran H,Mosquera JM,Puca L.Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer..Nature medicine2016;22:298-305 PMCID:PMC4777652

[12] Liu C,Zhu Y,Nadiminty N.Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer..Cancer Res2015;75:1413-22 PMCID:PMC4383695

[13] Grasso CS,Robinson DR,Dhanasekaran SM.The mutational landscape of lethal castration-resistant prostate cancer..Nature2012;487:239-43 PMCID:PMC3396711

[14] Beltran H,Frampton GM,Downing SR.Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity..Eur Urol2013;63:920-6 PMCID:PMC3615043

[15] Hara T,Araki H,Kanzaki N.Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome..Cancer Res2003;63:149-53

[16] Veldscholte J,Ris-Stalpers C,Jenster G.The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens..J Steroid Biochem Mol Biol1992;41:665-9

[17] Joseph JD,Qian J,Shao G.A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509..Cancer Discov2013;3:1020-9

[18] Balbas MD,Hosfield DJ,Arora VK.Overcoming mutation-based resistance to antiandrogens with rational drug design..Elife2013;2:e00499 PMCID:PMC3622181

[19] Rathkopf DE,Fox JJ,Slovin SF.Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer..J Clin Oncol2013;31:3525-30 PMCID:PMC3782148

[20] Hu R,Wei S,Veltri RW.Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer..Cancer Res2009;69:16-22 PMCID:PMC2614301

[21] Guo Z,Sun F,Linn DE.A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth..Cancer Res2009;69:2305-13 PMCID:PMC2672822

[22] Sun S,Vessella RL,Soriano K.Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant..J Clinical Invest2010;120:2715-30 PMCID:PMC2912187

[23] Ahrens-Fath I,Geserick C.Androgen receptor function is modulated by the tissue-specific AR45 variant..FEBS J2005;272:74-84

[24] Kohli M,Hillman DW,Henzler C.Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance..Clin Cancer Res2017;23:4704-15 PMCID:PMC5644285

[25] Antonarakis ES,Wang H,Nakazawa M.AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer..N Engl J Med2014;371:1028-38 PMCID:PMC4201502

[26] Zhang X,Sun S,Nelson PS.Androgen receptor variants occur frequently in castration resistant prostate cancer metastases..PLoS One2011;6:e27970 PMCID:PMC3219707

[27] Hornberg E,Crnalic S,Stattin P.Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival..PLoS One2011;6:e19059 PMCID:PMC3084247

[28] Dehm SM,Heemers HV,Tindall DJ.Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance..Cancer Res2008;68:5469-77 PMCID:PMC2663383

[29] Li Y,Fan D,Tewfik AH.Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression..Cancer Res2011;71:2108-17 PMCID:PMC3059379

[30] Mostaghel EA,Plymate SR,Balk S.Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants..Clin Cancer Res2011;17:5913-25 PMCID:PMC3184252

[31] Li Y,Brand LJ,Silverstein KA.Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines..Cancer Res2013;73:483-9 PMCID:PMC3549016

[32] Watson PA,Balbas MD,Socci ND.Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor..Proc Natl Acad Sci U S A2010;107:16759-65 PMCID:PMC2947883

[33] Hu R,Mostaghel EA,Gurel M.Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer..Cancer Res2012;72:3457-62 PMCID:PMC3415705

[34] Hu R,Luo J.A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities..Prostate2011;71:1656-67 PMCID:PMC3360954

[35] Cronauer MV,Eder IE,Culig Z.Basic fibroblast growth factor levels in cancer cells and in sera of patients suffering from proliferative disorders of the prostate..Prostate1997;31:223-33

[36] Luo J,Balk SP,Burnstein K.Role of androgen receptor variants in prostate cancer: report from the 2017 Mission Androgen Receptor Variants Meeting..Eur Urol2018;73:715-23 PMCID:PMC5929166

[37] Chan SC,Dehm SM.Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal..J Biol Chem2012;287:19736-49 PMCID:PMC3366007

[38] Liu C,Zhu Y,Schwartz CT.Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer..Clin Cancer Res2014;20:3198-210 PMCID:PMC4058390

[39] Nadiminty N,Lou W,Gao AC.NF-kappaB2/p52 enhances androgen-independent growth of human LNCaP cells via protection from apoptotic cell death and cell cycle arrest induced by androgen-deprivation..Prostate2008;68:1725-33

[40] Nadiminty N,Tepper C.Microarray analysis reveals potential target genes of NF-kappaB2/p52 in LNCaP prostate cancer cells..Prostate2010;70:276-87

[41] Nadiminty N,Liu C,Lou W.NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants..Mol Cancer Ther2013;12:1629-37 PMCID:PMC3941973

[42] Moigne RL,Obst JK,Jian K.Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor..J Clin Oncol2019;37:257

[43] Fronsdal K,Slagsvold T.CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1..J Biol Chem1998;273:31853-9

[44] Bevan CL,Claessens F,Parker MG.The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1..Mol Cell Biol1999;19:8383-92 PMCID:PMC84931

[45] Ueda T,Bruchovsky N.Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells..J Biol Chem2002;277:38087-94

[46] Reid J,Watt K,McEwan IJ.The androgen receptor interacts with multiple regions of the large subunit of general transcription factor TFIIF..J Biol Chem2002;277:41247-53

[47] Gao N,Rao MA,Mirosevich J.The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes..Mol Endocrinol2003;17:1484-507

[48] Hsieh CL,Gao S,Van Allen EM.PLZF, a tumor suppressor genetically lost in metastatic castration-resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy..Cancer Res2015;75:1944-8 PMCID:PMC4433564

[49] Agoulnik IU,Bingman WE3rd,Frolov A.Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression..Cancer Res2005;65:7959-67

[50] Agoulnik IU,Nakka M,Bingman WE3rd.Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer..Cancer Res2006;66:10594-602

[51] Comuzzi B,Schmidt S,Lodde M.The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer..J Pathol2004;204:159-66

[52] Debes JD,Lohse CM,Haugen DA.p300 in prostate cancer proliferation and progression..Cancer Res2003;63:7638-40

[53] Zhou HJ,Luo W,Lin SH.SRC-3 is required for prostate cancer cell proliferation and survival..Cancer Res2005;65:7976-83

[54] Tran C,Clegg NJ,Watson PA.Development of a second-generation antiandrogen for treatment of advanced prostate cancer..Science2009;324:787-90 PMCID:PMC2981508

[55] Yang YC,Mawji NR,Kato M.Targeting androgen receptor activation function-1 with EPI to overcome resistance mechanisms in castration-resistant prostate cancer..Clin Cancer Res2016;22:4466-77 PMCID:PMC5010454

[56] Luisi BF,Otwinowski Z,Yamamoto KR.Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA..Nature1991;352:497-505

[57] Savory JG,Lamprecht C,Walther RF.Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces..Mol Cell Biol2001;21:781-93 PMCID:PMC86670

[58] Galon J,Hiroi N,Boettner A.Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells..FASEB J2002;16:61-71

[59] Lu NZ,Grissom SF.Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor..Mol Cell Biol2007;27:7143-60 PMCID:PMC2168898

[60] Ren R,Cruz-Topete D.Dual role for glucocorticoids in cardiomyocyte hypertrophy and apoptosis..Endocrinology2012;153:5346-60 PMCID:PMC3473206

[61] Arora VK,Murali R,Wongvipat J.Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade..Cell2013;155:1309-22 PMCID:PMC3932525

[62] Kiemer AK,Quinlan MP.Identification of genes involved in epithelial-mesenchymal transition and tumor progression..Oncogene2001;20:6679-88

[63] Iwano M,Danoff TM,Okada H.Evidence that fibroblasts derive from epithelium during tissue fibrosis..J Clin Invest2002;110:341-50 PMCID:PMC151091

[64] Janda E,Killisch I,Herzig M.Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways..J Cell Biol2002;156:299-313 PMCID:PMC2199233

[65] Xue C,Venkov C,Neilson EG.The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis..Cancer Res2003;63:3386-94

[66] Liu Q,Liu G,Do K.Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-beta1/STAT3 axis-regulated EMT..Cell Death Dis2017;8:e3007 PMCID:PMC5596596

[67] Miao L,Li R,Crespo M.Disrupting androgen receptor signaling induces Snail-mediated epithelial-mesenchymal plasticity in prostate cancer..Cancer Res2017;77:3101-12

[68] Martin SK,Penticuff JC,Horbinski C.Multinucleation and mesenchymal-to-epithelial transition alleviate resistance to combined cabazitaxel and antiandrogen therapy in advanced prostate cancer..Cancer Res2016;76:912-26 PMCID:PMC4755804

[69] Ware KE,Schaeffer D,Zhang T.Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer..Oncotarget2016;7:50507-21 PMCID:PMC5226599

[70] Kong D,Li Y,Sakr WA.Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes..Prostate2015;75:161-74 PMCID:PMC4270852

[71] Cai C,Ng P,Nelson PS.Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors..Cancer Res2011;71:6503-13 PMCID:PMC3209585

[72] Ishizaki F,Kawasaki T,Hara N.Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer..Sci Rep2013;3:1528 PMCID:PMC3607121

[73] Locke JA,Lubik AA,Hendy SC.Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer..Cancer Res2008;68:6407-15

[74] Mohler JL,Bai S,Lih FB.Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer..Cancer Res2011;71:1486-96 PMCID:PMC3075600

[75] Fankhauser M,Macintyre G,Hong MK.Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer..Clin Cancer Res2014;20:5547-57

[76] Labrie F,Lin SX,Simard J.The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology..Steroids1997;62:148-58

[77] Bauman DR,Williams MV,Penning TM.Identification of the major oxidative 3alpha-hydroxysteroid dehydrogenase in human prostate that converts 5alpha-androstane-3alpha, 17beta-diol to 5alpha-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease..Mol endocrinol2006;20:444-58

[78] Geng H,Mendonca J,Liu Q.Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy..Nat commun2018;9:4972 PMCID:PMC6255907

[79] Massie CE,Ramos-Montoya A,Stark R.The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis..EMBO J2011;30:2719-33 PMCID:PMC3155295

[80] Tsouko E,White MA,Shi Y.Regulation of the pentose phosphate pathway by an androgen receptor-mTOR-mediated mechanism and its role in prostate cancer cell growth..Oncogenesis2014;3:e103 PMCID:PMC4035695

[81] Reina-Campos M,Duran A,L’Hermitte A.Increased serine and one-carbon pathway metabolism by PKClambda/iota deficiency promotes neuroendocrine prostate cancer..Cancer Cell2019;35:385-400.e9 PMCID:PMC6424636

[82] Ku SY,Wang Y,Seshadri M.Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance..Science2017;355:78-83 PMCID:PMC5367887

[83] Mu P,Benelli M,Hoover E.SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer..Science2017;355:84-8 PMCID:PMC5247742

[84] Bishop JL,Vahid S,Ketola K.The master neural transcription factor BRN2 is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer..Cancer Discov2017;7:54-71

[85] Beltran H,Park K,Sboner A.Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets..Cancer Discov2011;1:487-95 PMCID:PMC3290518

[86] Dardenne E,Benelli M,Berger A.N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer..Cancer Cell2016;30:563-77 PMCID:PMC5540451

[87] Mosquera JM,Park K,Robinson BD.Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer..Neoplasia2013;15:1-10 PMCID:PMC3556934

[88] Yin Y,Chang Y,Chen X.N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway..Mol Cancer2019;18:11 PMCID:PMC6337850