Tribbles 2 pseudokinase confers enzalutamide resistance in prostate cancer by promoting lineage plasticity

Abstract

Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching. Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching. Enzalutamide, an inhibitor of androgen receptor (AR) function, is a popular drug commonly prescribed to treat advanced prostate cancer, but resistant prostate cancer eventually develops which grow aggressively, leading to widespread metastatic disease and ends up with a lethal outcome (1Armstrong A.J. Szmulewitz R.Z. Petrylak D.P. Holzbeierlein J. Villers A. Azad A. Alcaraz A. Alekseev B. Iguchi T. Shore N.D. Rosbrook B. Sugg J. Baron B. Chen L. Stenzl A. Arches: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer.J. Clin. Oncol. 2019; 37: 2974-2986Google Scholar, 2Kregel S. Chen J.L. Tom W. Krishnan V. Kach J. Brechka H. Fessenden T.B. Isikbay M. Paner G.P. Szmulewitz R.Z. Vander Griend D.J. Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer.Oncotarget. 2016; 7: 26259-26274Google Scholar, 3Tucci M. Zichi C. Buttigliero C. Vignani F. Scagliotti G.V. Di Maio M. Enzalutamide-resistant castration-resistant prostate cancer: Challenges and solutions.Onco. Targets Ther. 2018; 11: 7353-7368Google Scholar). Based on present assessment, the enzalutamide resistant type of aggressive prostate cancer is responsible for most of the morbidity and mortality associated with prostate cancer and ∼30,000 lives of American men are lost every year (4Miller K.D. Fidler-Benaoudia M. Keegan T.H. Hipp H.S. Jemal A. Siegel R.L. Cancer statistics for adolescents and young adults, 2020.CA Cancer J. Clin. 2020; 70: 443-459Google Scholar). Nevertheless, the lack of proper understanding about critical molecular targets in hormone refractory, enzalutamide-resistant prostate cancer cells, largely contributes to majority of the prostate cancer fatalities. Clinical manifestation of drug resistance is the result of selective growth of cell clones that are either intrinsically capable of or have acquired the power to resist drug’s effects on critical survival mechanisms. However, knowledge about signaling mechanisms that play active roles in the progression phase of prostate cancer to enzalutamide resistance is still limited, which is a delaying progress toward the development of a long-term, effective therapeutic strategy. Common forms of prostate cancer cells bear luminal characteristics and depend on androgenic signaling for survival and growth, which is the basis for antiandrogenic therapy. However, it has been realized that men with prostate cancer who were treated with antiandrogenic therapies frequently develop aggressive and deadly forms of prostate cancers, which are no longer responsive to androgen-blockade therapies. Several reports encompassing the involvement of both AR reactivation or bypass, as well as androgen-independent signaling, have been forwarded to explain the mechanism of enzalutamide resistance. However, analysis of multiple cell lines and in vivo models, which were used to explore the molecular basis, have ended up with identification of cancer cell subtypes (5Blatt E.B. Raj G.V. Molecular mechanisms of enzalutamide resistance in prostate cancer.Cancer Drug Resist. 2019; 2: 189-197Google Scholar, 6Chen W.S. Aggarwal R. Zhang L. Zhao S.G. Thomas G.V. Beer T.M. Quigley D.A. Foye A. Playdle D. Huang J. Lloyd P. Lu E. Sun D. Guan X. Rettig M. et al.Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer.Eur. Urol. 2019; 76: 562-571Google Scholar). Current molecular understanding suggests that in addition to AR reactivation by mutation or splice variants, manifestation of enzalutamide resistance can be the result of overgrowth of cells that are developed in the tumor by lineage switching which may be triggered by drug-induced repression or loss of the AR-signaling (7Akamatsu S. Inoue T. Ogawa O. Gleave M.E. Clinical and molecular features of treatment-related neuroendocrine prostate cancer.Int. J. Urol. 2018; 25: 345-351Google Scholar, 8Beltran H. Prandi D. Mosquera J.M. Benelli M. Puca L. Cyrta J. Marotz C. Giannopoulou E. Chakravarthi B.V. Varambally S. Tomlins S.A. Nanus D.M. Tagawa S.T. Van Allen E.M. Elemento O. et al.Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.Nat. Med. 2016; 22: 298-305Google Scholar, 9Labrecque M.P. Coleman I.M. Brown L.G. True L.D. Kollath L. Lakely B. Nguyen H.M. Yang Y.C. da Costa R.M.G. Kaipainen A. Coleman R. Higano C.S. Yu E.Y. Cheng H.H. Mostaghel E.A. et al.Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer.J. Clin. Invest. 2019; 129: 4492-4505Google Scholar). About 10 to 20% of enzalutamide-resistant prostate cancers show neuroendocrine (NE) features and no effective treatments are currently available for this type of aggressive and highly invasive prostate cancer (10Davies A.H. Beltran H. Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer.Nat. Rev. Urol. 2018; 15: 271-286Google Scholar, 11Beltran H. Hruszkewycz A. Scher H.I. Hildesheim J. Isaacs J. Yu E.Y. Kelly K. Lin D. Dicker A. Arnold J. Hecht T. Wicha M. Sears R. Rowley D. White R. et al.The role of lineage plasticity in prostate cancer therapy resistance.Clin. Cancer Res. 2019; 25: 6916-6924Crossref Scopus (91) Google Scholar, 12Handle F. Prekovic S. Helsen C. Van den Broeck T. Smeets E. Moris L. Eerlings R. Kharraz S.E. Urbanucci A. Mills I.G. Joniau S. Attard G. Claessens F. Drivers of AR indifferent anti-androgen resistance in prostate cancer cells.Sci. Rep. 2019; 9: 13786Google Scholar). Though the continued growth and metastasis of the heavily enzalutamide-treated prostate tumors can be driven by nonandrogenic signaling, molecular underpinnings of critical targetable mechanisms in treatment-emergent NE type prostate cancer cells are yet to be fully characterized. When prostate cancer cells become resistant to strong androgen-receptor blockers, such as enzalutamide, their common characteristics change from slow-growing and noninvasive to fast-growing, highly invasive type, but the knowledge about critical signaling mechanisms driving rapid growth and resistance to enzalutamide is still limited. To better understand the mechanistic basis behind enzalutamide resistance, we developed an in vitro model by chronically treating human LNCaP, MDA-PCa-2B, and LAPC4 prostate cancer cells (AR-signaling intact) with gradually increasing doses of enzalutamide (up to 30 μM) for >12 weeks to mimic the clinical conditions in standard long-term enzalutamide therapy (13Monga J. Subramani D. Bharathan A. Ghosh J. Pharmacological and genetic targeting of 5-lipoxygenase interrupts c-Myc oncogenic signaling and kills enzalutamide-resistant prostate cancer cells via apoptosis.Sci. Rep. 2020; 10: 6649Google Scholar). The resultant cells (LNCaP-ENR, PCa-2B-ENR, and LAPC4-ENR) are completely resistant to clinically relevant doses of enzalutamide, the blood level of which goes up to ∼34 μM in average (14Gibbons J.A. Ouatas T. Krauwinkel W. Ohtsu Y. van der Walt J.S. Beddo V. de Vries M. Mordenti J. Clinical pharmacokinetic studies of enzalutamide.Clin. Pharmacokinet. 2015; 54: 1043-1055Google Scholar, 15Gibbons J.A. Vries M. Krauwinkel W. Ohtsu Y. Noukens J. van der Walt V. Mol R. Mordenti J. Ouatas T. Pharmacokinetic drug interaction studies with enzalutamide.Clin. Pharmacokinet. 2015; 54: 1057-1069Google Scholar). By gene expression array, RT-PCR, and Western blot, we found that enzalutamide-resistant prostate cancer cells overexpress Tribbles 2 (TRIB2), a member of the Tribbles found that overexpression of TRIB2 by gene can resistance to doses of enzalutamide. Interestingly, molecular revealed that the overexpression of TRIB2 luminal characteristics and NE features involving the neuronal transcription BRN2 and the stemness SOX2 (SRY-box Moreover, inhibition of either TRIB2 or its targets or resensitizes resistant cells to enzalutamide. that TRIB2 is a new for prostate cancer and that TRIB2 may to enzalutamide resistance in prostate cancer cells, in by lineage plasticity and phenotype switching. A gene expression analysis revealed that the TRIB2 is in enzalutamide-resistant and prostate cancer cells, to enzalutamide and cells To the we TRIB2 expression by RT-PCR, and Western strong of TRIB2 in enzalutamide-resistant (LNCaP-ENR, PCa-2B-ENR, and LAPC4-ENR) prostate cancer cells and of TRIB2 is with of the increased of and increased level of which are standard markers that cell survival and in a of cells. with we found of TRIB2 in gene expression in enzalutamide-resistant prostate cancer cells J.L. D. S. A. K. H. R. A. F. L. Gleave M.E. Lin D. et al.The transcription factor BRN2 is an androgen of neuroendocrine in prostate cancer.Cancer 7: Scholar). Enzalutamide-resistant cells increased of TRIB2 to cells expression of TRIB2 as by et M. E. of androgen metastatic prostate cancer cells of the Urol. in the and prostate cancer cells to cells. To the in vitro of TRIB2 overexpression is in we comprehensively analyzed prostate tumors in found that of prostate tumors overexpress TRIB2 the were treated with enzalutamide 30 for weeks and Moreover, we found that a majority of the clinically advanced metastatic prostate tumors from enzalutamide-treated show a in the expression of TRIB2 and these that of TRIB2 overexpression is a mechanism in prostate cancer cells both in vitro and in vivo treated with enzalutamide, a second-generation inhibitor of AR To the of TRIB2 we used a of and cell lines and tumor and analyzed by both Western as well as overexpression of TRIB2 in prostate cancer cells upon enzalutamide both in vitro and in we the TRIB2 role in enzalutamide-resistant cells. By we found that of TRIB2 the viability and growth of enzalutamide-resistant cells, cells and suggesting that TRIB2 a critical but selective role in enzalutamide-resistant prostate cancer cells. found that TRIB2 tumor growth in and inhibitor of TRIB2 is However, it that the TRIB2 by and TRIB2 for doses D.M. D.P. W. S. S. K. C. of induce of human Tribbles 2 in cancer cells.Sci. 2018; Scholar). Thus, we the of and found that it downregulates TRIB2 level and kills enzalutamide-resistant prostate cancer cells by that TRIB2 an role in enzalutamide-resistant cells and that selective be developed to enzalutamide-resistant prostate cancer cells. TRIB2 a critical role in the viability of enzalutamide-resistant prostate cancer cells, it has as a new molecular for therapeutic the overexpression of TRIB2 growth or an active role in resistant prostate cancer cells for their enzalutamide therapy. To we and cells with human TRIB2 gene and found that the cells and show increased of and and level of a tumor cells increased and of and increased to in suggesting that TRIB2 may play a role as a to aggressive which is frequently in antiandrogenic prostate cancer cells. found that overexpression of TRIB2 prostate cancer cells resistant to therapeutic doses of enzalutamide, and the enzalutamide-resistant cells are to the and Interestingly, this resistance is and the cells become to enzalutamide treated with or to enzalutamide in and cells TRIB2 found that the castration-resistant prostate cancer cells, to upon TRIB2 cells and show no to enzalutamide we found that overexpression of TRIB2 prostate tumor growth in and these tumors grow with enzalutamide and that TRIB2 the aggressive but contributes to the enzalutamide resistance mechanism in prostate cancer cells. TRIB2 confers resistance to enzalutamide is an to may of the overexpression or mutation of the AR or to development of mechanism(s) of androgenic To the downstream mechanism of TRIB2 in enzalutamide resistance, we found that enzalutamide-resistant cells and show a in the level of luminal markers 8 and but is a strong in the expression of NE such as and A and that resistance to enzalutamide reactivation of the AR or of the luminal TRIB2 to be in transdifferentiation of luminal cells to develop characteristics analysis of enzalutamide-resistant prostate cancer cells by and J.L. D. S. A. K. H. R. A. F. L. Gleave M.E. Lin D. et al.The transcription factor BRN2 is an androgen of neuroendocrine in prostate cancer.Cancer 7: revealed a the expression of TRIB2 and AR we found a strong of the neuronal transcription and the stemness transcription SOX2, in enzalutamide-resistant cells A and and which were to lineage plasticity in prostate cancer cells J.L. D. S. A. K. H. R. A. F. L. Gleave M.E. Lin D. et al.The transcription factor BRN2 is an androgen of neuroendocrine in prostate cancer.Cancer 7: Scholar, P. Zhang Benelli M. E. Chen J. D. W. Prandi D. et lineage plasticity and resistance in and prostate Scholar). The of NE and stemness markers by TRIB2 by of TRIB2 in cells found overexpression of NE markers and of AR in cells in tumor in and Moreover, we found strong expression of TRIB2 in multiple standard prostate tumor and the Beltran and show overexpression of TRIB2 in prostate cancers to and Interestingly, inhibition of either BRN2 or SOX2 resensitizes cells to enzalutamide that the molecular mechanism of TRIB2 may of BRN2 and SOX2, to cellular plasticity that TRIB2 prostate cancer cells to enzalutamide by switching their from luminal to NE characteristics. Thus, it that a strong TRIB2 overexpression and the development of NE features in prostate cancer cells. of androgenic signaling has been to the of strong AR the is and resistance invariably develops which therapy (5Blatt E.B. Raj G.V. Molecular mechanisms of enzalutamide resistance in prostate cancer.Cancer Drug Resist. 2019; 2: 189-197Google Scholar, 6Chen W.S. Aggarwal R. Zhang L. Zhao S.G. Thomas G.V. Beer T.M. Quigley D.A. Foye A. Playdle D. Huang J. Lloyd P. Lu E. Sun D. Guan X. Rettig M. et al.Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer.Eur. Urol. 2019; 76: 562-571Google Scholar, S. Inoue T. Ogawa O. Gleave M.E. Clinical and molecular features of treatment-related neuroendocrine prostate cancer.Int. J. Urol. 2018; 25: 345-351Google Scholar). has been realized that enzalutamide-resistant prostate cancer frequently deadly phenotype mechanisms the of which is yet to be fully characterized. that overexpression of TRIB2 upon with enzalutamide, both in vitro and in vivo of the overexpression of TRIB2 by enzalutamide and the aggressive growth characteristics of cells a of AR therapy for prostate Though of TRIB2 in prostate cancer cells upon enzalutamide is a and TRIB2 is in these cells is this the of roles in enzalutamide resistance, of of gene expression to be found that and prostate cancer cells that are in AR of TRIB2 Interestingly, overexpression and of AR downregulates TRIB2 suggesting a of TRIB2 by AR of the neuronal transcription factor and by AR has been found J.L. D. S. A. K. H. R. A. F. L. Gleave M.E. Lin D. et al.The transcription factor BRN2 is an androgen of neuroendocrine in prostate cancer.Cancer 7: Scholar, R. V. A. D. S. M. F. M. Zoubeidi A. Beltran H. B. deprivation upregulates expression and cellular plasticity in prostate cancer.Nat. 2020; 11: Scholar). The aggressive of prostate cancer cells well with aggressive and cancer cells which overexpress TRIB2. in of the of strong androgenic signaling in and cells, the of which may the expression of TRIB2 in prostate cells. However, is to this the of TRIB2 overexpression in prostate cancer cells upon enzalutamide TRIB2 in as a regulator of J. S. A. P. Tribbles and in by Scholar). its expression in human and as well as a role in cancer cells were R. B. S. L. M. A. S. A. E. M. W. TRIB2 confers resistance to therapy by the Scholar, K. Tribbles in the The roles of in and Scholar). to TRIB2 role in enzalutamide-resistant prostate cancer cells. Interestingly, we that with TRIB2 level and the viability of enzalutamide-resistant cells, suggesting that TRIB2 a critical role in the enzalutamide resistance mechanism in prostate cancer cells overexpression of TRIB2 can resistance to doses of enzalutamide is However, a revealed from is the resistance of prostate cancer cells to second-generation that are frequently used in the in addition to enzalutamide, such as and enzalutamide-resistant cells show level of luminal markers and and increased the level of NE markers and and these characteristics are TRIB2 is by A and that TRIB2 is a for transdifferentiation of prostate cancer cells from luminal to NE AR stemness as well as NE were in enzalutamide-resistant prostate cancer cells and tumors H. Prandi D. Mosquera J.M. Benelli M. Puca L. Cyrta J. Marotz C. Giannopoulou E. Chakravarthi B.V. Varambally S. Tomlins S.A. Nanus D.M. Tagawa S.T. Van Allen E.M. Elemento O. et al.Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.Nat. Med. 2016; 22: 298-305Google Scholar, 9Labrecque M.P. Coleman I.M. Brown L.G. True L.D. Kollath L. Lakely B. Nguyen H.M. Yang Y.C. da Costa R.M.G. Kaipainen A. Coleman R. Higano C.S. Yu E.Y. Cheng H.H. Mostaghel E.A. et al.Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer.J. Clin. Invest. 2019; 129: 4492-4505Google Scholar, A.H. Beltran H. Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer.Nat. Rev. Urol. 2018; 15: 271-286Google Scholar, 11Beltran H. Hruszkewycz A. Scher H.I. Hildesheim J. Isaacs J. Yu E.Y. Kelly K. Lin D. Dicker A. Arnold J. Hecht T. Wicha M. Sears R. Rowley D. White R. et al.The role of lineage plasticity in prostate cancer therapy resistance.Clin. Cancer Res. 2019; 25: 6916-6924Crossref Scopus (91) Google Scholar, 12Handle F. Prekovic S. Helsen C. Van den Broeck T. Smeets E. Moris L. Eerlings R. Kharraz S.E. Urbanucci A. Mills I.G. Joniau S. Attard G. Claessens F. Drivers of AR indifferent anti-androgen resistance in prostate cancer cells.Sci. Rep. 2019; 9: 13786Google Scholar, D. E. Beer T.M. Thomas G.V. E. Aggarwal R. J. S. S. Quigley D.A. Guan X. Foye A. et profiling an androgen receptor stemness associated with enzalutamide S. A. 2020; Scholar, R. Huang J. Zhang L. Thomas G.V. V. Zhang C. Lloyd P. Gleave M. J. Beer T.M. et clinical and of treatment-emergent neuroendocrine prostate cancer: A Clin. Oncol. 2018; Scholar). the lineage plasticity and development of NE phenotype have been in P. Zhang Benelli M. E. Chen J. D. W. Prandi D. et lineage plasticity and resistance in and prostate Scholar, S. Y. P. M. D.P. J. B. Brown M. M. et and to prostate cancer lineage and Scholar). Moreover, a role of BRN2 in treatment-emergent NE via of SOX2 J.L. D. S. A. K. H. R. A. F. L. Gleave M.E. Lin D. et al.The transcription factor BRN2 is an androgen of neuroendocrine in prostate cancer.Cancer 7: Scholar). found that the overexpression of TRIB2 upregulates BRN2 and Moreover, inhibition of either BRN2 or SOX2 resensitizes cells to enzalutamide suggesting that the NE characteristics may play an role in enzalutamide resistance. of cellular characteristics is an that the molecular mechanism of TRIB2 of BRN2 and SOX2, to cellular plasticity and lineage switching. Based on it that TRIB2 lineage switching by stemness and NE which enzalutamide-resistant prostate cancer cells in a that are no longer to depend on of AR tumors have been found to in as as of the treated with such as enzalutamide, and this is to up with to the AR J. and of androgen receptor signaling in advanced prostate Scholar, T. K. A. of prostate cancer cells inhibition of AR of 9: Scholar). found a strong of TRIB2 in a range of prostate tumor and we that the overexpression of TRIB2 NE features in prostate cancer cells, and this is with inhibition of TRIB2. Thus, TRIB2 emerges as a new a that prostate cancer cells to enzalutamide by switching their from the luminal type and NE characteristics. TRIB2 is to the and and a role in J. S. A. P. Tribbles and in by Scholar). TRIB2 to and via a still mechanism to aggressive cancer growth and therapeutic resistance R. B. S. L. M. A. S. A. E. M. W. TRIB2 confers resistance to therapy by the Scholar, K. Tribbles in the The roles of in and Scholar). in prostate cancer, it that TRIB2 is a for growth and enzalutamide resistance and via a mechanism involving the of lineage plasticity and transdifferentiation that prostate cancer cells can the loss of by of the androgenic signaling LNCaP, MDA-PCa-2B, LAPC4 human prostate cancer cell lines and cell were from American The enzalutamide-resistant and cells were by treating with the increasing of enzalutamide The castration-resistant and enzalutamide-resistant and cells were by Zoubeidi The cells were in or or the were with and the enzalutamide-resistant cells were in the of 30 μM enzalutamide. from cells and in the by the and were the the The analysis of a model as in the in R. A gene with a 2 and a is The of the in R. that it has a of and a of The the gene the in R. and of used for III to the gene expression were in and were used to the expression level of the to used as a were in and to were treated with the cells were and in 10 10 and a of were by and to The were with and with by The were by from To be as were analyzed in SOX2, and were from and were from with enzalutamide-treated prostate cancer were from the Cancer of and of The hormone prostate tumor were from from the from tumors and enzalutamide were from E. were for and in in a The were in for by with for with with a 10 The were with in The were and with or 2 for 30 The were developed and with for The were in and The were and the by analysis were as a from for and the targeting BRN2 and SOX2 were from of used in with the The cells were in and treated with or cell viability by and cells were in of and on the of a 2 of were to and the were with 2 The cells were treated with enzalutamide μM) for growth and enzalutamide were every the of the cells were with and the were and a studies were by the and and to the for and To the of TRIB2 on the growth on prostate tumors in cells in in were the of When the tumors to were and treated either with or TRIB2 from via every for To study the of TRIB2 overexpression on enzalutamide resistance in or cells were the or of and to grow the tumors were The were to either or enzalutamide for growth by a by either or with multiple or the The of as The are as the from and are in the are available either in the or in the J.L. D. S. A. K. H. R. A. F. L. Gleave M.E. Lin D. et al.The transcription factor BRN2 is an androgen of neuroendocrine in prostate cancer.Cancer 7: Scholar, S. Y. P. M. D.P. J. B. Brown M. M. et and to prostate cancer lineage and Scholar). The that have no of with the of this E. Gleave of the for and of the Cancer for the from for is by the of Cancer Cancer J. M. and J. G. J. and J. G. J. D. J. J. H. A. and J. G. J. D. J. J. H. A. and J. G. J. C. S. H. A. and J. G. and J. C. S. D. J. J. H. A. and J. G. J. M. and J. G. J. D. and J. G. by the and by the to J. G. by the the Cancer the and the Drug and and to J. J. A.

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