ISSN 00268933, Molecular Biology, 2015, Vol. 49, No. 5, pp. 638–648. © Pleiades Publishing, Inc., 2015. Original Russian Text © G.S. Krasnov, A.A. Dmitriev, A.F. Sadritdinova, N.N. Volchenko, E.N. Slavnova, T.V. Danilova, A.V. Snezhkina, N.V. Melnikova, M.S. Fedorova, V.A. Lakunina, A.A. Belova, K.M. Nyushko, B.Y. Alekseev, A.D. Kaprin, A.V. Kudryavtseva, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 5, pp. 716–727.
REVIEWS UDC 577.0,616006
Molecular Genetic Mechanisms of Drug Resistance in Prostate Cancer G. S. Krasnova, b, c, A. A. Dmitrieva, b, A. F. Sadritdinovaa, N. N. Volchenkob, E. N. Slavnovab, T. V. Danilovab, A. V. Snezhkinaa, N. V. Melnikovaa, M. S. Fedorovaa, V. A. Lakuninaa, A. A. Belovaa, K. M. Nyushkob, B. Y. Alekseevb, A. D. Kaprinb, and A. V. Kudryavtsevaa, b a
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia; email:
[email protected] b Herzen Moscow Cancer Research Institute, Ministry of Health of the Russian Federation, Moscow, 125284 Russia c Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, 119121 Russia Received December 25, 2014; in final form, March 7, 2015
Abstract—Drug resistance and especially crossresistance are the most important problems of therapy of prostate cancer. Drug resistance mechanisms, including liganddependent (requiring the presence of andro gens in the cell) and independent (not requiring androgens) ones, are reviewed. The mechanisms are mainly based on mutations of the androgen receptor (AR) gene, expression of aberrant constitutively active AR splice variants, and upregulation of androgen synthesis genes. DOI: 10.1134/S0026893315050118 Keywords: prostate cancer, drug resistance, androgen receptor, androgens, abiraterone, enzalutamide, muta tions, splice variants
INTRODUCTION Cancer cells are capable of adaptation leading to drug resistance, which is the main problem of therapy in virtually all cancers, including prostate cancer (PC). Although a broad range of anticancer agents, including investigational products and drugs approved for human use, is available, the majority of them lose their therapeutic efficacy with time [1]. The andro gendependent pathway is still a main target in PC, which is the second in incidence and the first in mor tality among oncology diseases in the global popula tion [2]. The androgen receptor (AR) is a key element of the pathway. Inactive AR usually occurs in the cyto plasm. Once bound with a ligand (testosterone or dihydrotestosterone, DHT), AR is transferred into the nucleus and acts as a transcription factor (TF) to induce expression of various genes responsible for reg ulating cell proliferation and differentiation. In the vast majority of cases, PC is sensitive to the blood testosterone level during early therapy. Thus reducing androgen availability suppresses or delays the disease progression. However, drug resistance inevita Abbreviations: ADT, androgen deprivation therapy; AR, andro gen receptor; GR, glucocorticoid receptor; DHT, dihydrotest osterone; DHEA, dehydroepiandrosterone; PC, prostate can cer; CRPC, castrationresistant PC; TF, transcription factor; DBD, DNAbinding domain; NTD, Nterminal domain; LBD, ligandbinding domain; PSA, prostatespecific antigen.
bly develops with time, leading to a rapid PC progres sion in androgen deprivation [1]. Several new drugs have recently come into clinical use to treat PC (including metastatic PC) progressing at limited androgen availability. Antiandrogen drugs, such as abiraterone and enzalutamide, stabilize the disease and delay the initiation of chemotherapy [3, 4]. Yet the tumor becomes resistant to the drugs with time and, what is more, develops crossresistance; i.e., resis tance to one drug determines a low efficacy of subse quent treatment with other drugs [5]. Tumors insensi tive to antiandrogens are a main problem of modern urooncology. The review considers various mechanisms respon sible for drug resistance in PC. The mechanisms can conventionally be divided into two large groups, androgen dependent (requiring testosterone for acti vation of the AR signaling pathway) and independent (not requiring testosterone). The drug resistance mechanisms includes AR mutations that extend the range of AR ligands; upregulation of genes involved in androgen synthesis; expression of aberrant constitu tively active AR splice variants, which do not require a ligand for activation; and many other mechanisms, which are considered below (figure).
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LIGANDDEPENDENT MECHANISMS OF DRUG RESISTANCE Upregulation of Genes Involved in Synthesis of Androgens and Import of Their Precursors One of the main approaches to therapy for primary PC is reducing the blood testosterone level by surgical castration or antihormonal therapy (chemical castra tion), which is more common. However, the procedure fails to permanently stop tumor growth or to cause complete cytoreduction. The tumor often responds to a lower testosterone availability by increasing the intra cellular import of weak cell androgens, including androstenedione, which is secreted by the adrenal cor tex [6]. Androstenedione can provide an additional source for synthesis of DHT, which is ten times as active as testosterone toward AR. DHT is normally synthesized from testosterone available in the cell by 5αreductase. Upregulation of genes involved in vari ous steps of androgen synthesis from other imported precursors is another mechanism that increases the androgen pool in the cancer cell [7–12]. Moreover, the AR gene is often overexpressed in cancer cells [13], the increase in expression resulting from amplification of the corresponding chromosome locus in some cases [14]. One of the key steps in androgen synthesis from steroid precursors is converting pregnenolone to 17αОНpregnenolone and then to dehydroepi androsterone (DHEA), which is normally secreted by the testis and adrenal cortex. The reactions are cata lyzed by cytochrome CYP17A1, which possesses both hydroxylase and lyase activities. Importing cholesterol or pregnenolone is the most available means to pro duce DHT for cancer cells in androgen deprivation, along with upregulation of the CYP17A1 gene and other genes involved in further steps of DHT synthesis [15–19]. As was observed in a model system (LNCaP cells injected intraperitoneally to mice), CYP17A1 expression increases and expression of alternative AR splice vari ants capable of ligandindependent activation is induced in cancer cells in response to androgen depri vation therapy (ADT) [20]. The CYP17A1 enzyme is a main target of abirater one, which is one of the new drugs effective in castra tionresistant PC (CRPC). The advantage is that abi raterone suppresses the production of close testoster one precursors in the adrenal cortex, testis, and tumor [21]. Androstenedione and other close testosterone precursors often persist in sufficient amounts in the blood after surgical castration and can be used effi ciently to synthesize testosterone and DHT by cancer cells [22]. Arbiraterone was shown to substantially suppress the production of steroid androgen precursors, although without radically reducing their blood con centration to a minimum. This circumstance explains, among other factors, why cancer cells remain capable of DHT synthesis due to increased import of the close DHT precursors that do not require hydrolase or lyase MOLECULAR BIOLOGY
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activity of CYP17A1 for conversion to DHT. In partic ular, DHEA sulfate persists at a low level, and DHEA resulting from sulfate group cleavage by steroid sulfa tase is enough to ensure the androgen production nec essary for maintaining cell proliferation [22]. LIGANDINDEPENDENT MECHANISMS OF DRUG RESISTANCE Splice Variants of the Androgen Receptor Gene Three domains normally occur in AR. A DNA binding domain (DBD) is in the central region of the AR polypeptide chain and is responsible for the direct interaction with target genes. The Nterminal domain (NTD) is involved in interacting with various tran scriptional coactivators and corepressors. The Cter minal ligandbinding domain (LBD) is responsible for a negative regulation of activity of the total protein. A deletion of the Cterminal domain renders AR consti tutively active; i.e., the aberrant AR splice variants (ARVs) that lack the LBD no longer require andro gens to enter the nucleus and to trigger expression of the target genes. Normally, AR occurs in the cyto plasm in complex with chaperone proteins, dissociates from them upon androgen binding, is transferred into the nucleus, binds to DNA in a dimeric form, and trig gers transcription of its target genes in cooperation with various cofactors. Expression of AR splice variants is one of the main ligandindependent mechanisms of crossresistance to abiraterone and other current ADT drugs, including enzalutamide [23–25]. Enzalutamide acts as an AR antagonist. Interacting with the LBD, enzalutamide prevents AR binding with androgens and thereby ren ders AR inactive and blocks its nuclear transport and expression of its target genes. Expression of AR splice variants is generally associated with CRPC progres sion and metastasis [26, 27]. At least 16 aberrant splice variants are known for AR [28]. The most common AR splice variants contain exon 3 (encodes for the Nterminal region of the DBD) linked to the following intron region, which harbors a stop codon. The downstream protein regions, includ ing the LBD, are lost as a result. Lack of the LBD ren ders AR constitutively active and affects the range of AR target genes [29]. Aberrations affecting the АR gene are one of the factors that determine synthesis of aberrant AR variants [30]. AR splice variant 7 (ARV7, or AR3) is best studied today. On recent evidence, ARV7 production starts in 40% of patients treated with enzalutamide (a direct AR inhibitor) and 20% patients treated with abirater one and is associated with a poor prognosis [31]. Various constitutively active aberrant AR splice variants are capable of entering the nucleus without the fulllength AR (ARFL) or producing dimers with ARFL to ensure its transport into the nucleus. The most common aberrant splice variants, ARV7 and
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Expression of AR splice variants (ARVs) DHT
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Development of drug resistance in PC. Androgendependent mechanisms: overexpression of the genes for the androgen receptor (AR) and androgen synthesis enzymes, increased import of androgen precursors, AR mutations that abolish the antagonist prop erties of enzalutamide and other drugs, AR posttranslational modification, and upregulation of AR coactivators. Androgeninde pendent mechanisms: expression of constitutively active AR splice forms, AR mutations that extend the range of AR ligands, and hyperactivation of glucocorticoid pathways.
ARv567es, were shown to facilitate ARFL nuclear translocation even in the absence of androgens in the cell [32, 33]. Enzalutamide, which inhibits the nuclear transport of ARFL, cannot efficiently suppress trans
location of the ARV and ARFL dimers into the nucleus [32]. Thus, expression of aberrant splice variants of AR is one of the main mechanisms of multiple drug resis MOLECULAR BIOLOGY
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tance and presents a substantial problem of PC ther apy. Clonal expansion of cells expressing AR splice variants often occurs in response to LBDtargeting AR antagonists, such as enzalutamide and bicalutamide. It seems necessary to design alternative AR inhibitors to target the NTD or DBD. The NTD is attractive as a therapeutic target because it harbors two sites, TAU1 and TAU5, respon sible for regulating transcriptional activity [34]. While more than 70 crystal structures are known for the AR LBD in complex with various ligands and inhibitors, there are no data on the threedimensional structures of the NTD and DBD. This circumstance hinders computerassisted prediction of a range of molecules targeting these two domains. Yet several NTDinter acting compounds have been identified to date [35]. Particular attention is attracted by five bisphenol derivatives, EPI001 to EPI005, which covalently bind to the NTD in both normal AR and its aberrant splice variants and block their further protein–protein interactions essential for activating transcription of the target genes [36, 37]. EPI001 and its analogs were observed to cause cytoreduction of CRPC cell xenografts in mice without exerting a pronounced toxic effet [36, 37]. Mutations of the Androgen Receptor Mutations of AR are another mechanism responsi ble for ADT resistance. AR mutations are usually undetectable in early carcinogenesis [38] and occur in a substantial portion (approximately 20%) of tumors at an advanced stage [39]. Several tens of mutations are known to change the AR function [40, 41]. The substitutions H874Y, T877A, and T877S are the most common. T877A was the first mutation identified to affect the protein function and occurs in the ligand binding pocket of AR [42, 43]. The mutation is found in almost onethird of prostate cancers with bone mar row metastasis [39]. Mutations in position 877 substan tially extent the range of AR ligands, so that AR is acti vated not only by testosterone and DHT, but also by other steroid hormones, including estrogen, progestin, and glucocorticoids. H874Y is another mutation known to extend the ligand range. Although position 874 is outside the ligandbinding pocket of AR, muta tions in this position cause separation of two αhelices involved in pocket formation, the pocket consequently grows larger, and the mutant AR loses its ligand speci ficity. Characteristic mutations were observed in the tumors from patients treated with various AR antago nists, including flutamide or bucalutamide. Mutations usually affect AR codons 874 and 877 in the case of flutamide treatment and codon 741 in the case of bicalutamide treatment. At the same time, AR muta tions are rare (less than 10% of tumors) in patients receiving ADT without AR antagonists [44, 45]. Mutations of AR codons 874, 877, and 741 confer MOLECULAR BIOLOGY
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resistance to AR antagonists. Moreover, bicalutamide, cyproterone, and flutamide and its derivatives act as agonists of mutant ARs containing these mutations [46]. The mechanism is associated with the socalled antiandrogen withdrawal syndrome; i.e., the progres sion rate of ADTrefractory PC grows substantially lower when AR antagonists are discontinued [47]. Enzalutamide resistance can also result from AR mutations (F876L). Compared with other AR antago nists, enzalutamide has the advantage of acting as weak agonist of mutant ARs. The antiandrogen with drawal syndrome is consequently lower in the case of enzalutamide treatment [48]. The effects of AR mutations are not restricted to the above. Depending on the mutation position and the ligand bound, AR interacts with different coactiva tors to trigger different transcription programs and thus to determine different tumor phenotypes [49]. For instance, the H847Y mutant has higher affinity to the coactivator p160 and, consequently, a higher oncogenic potential [50]. Drug resistance mutations of AR may provide a basis for designing highly selective targeted therapy of PC. Various agents are now known to selectively bind with mutant proteins whose mutations increase the oncogenic potential. For instance, two drugs, dab rafenib and vemurafenib, have been approved to treat melanoma and specifically inhibit the BRAF variants that have mutations in position 600 and are constitu tively active as a result [51, 52]. At least three new compounds have been obtained by chemical modifi cation of enzalutamide and are active toward AR bear ing the F876L mutation [53]. Posttranslational Modification of the Androgen Receptor Various posttranslational modifications of AR play a significant role in ADT resistance and cell prolifera tion elevated even in androgen depletion [54]. AR modification can affect the nuclear transport rate, reverse export into the cytoplasm, activity as a tran scription factor (TF), and proteasomal degradation rate of AR. AR modification involves many proteins, including Akt, SRC, CDK, ACK1, etc. AP is a target of the tyrosine kinases SRC and ACK1 and cyclin dependent serine kinases CDK1 and CDK9, which phosphorylate the NTD at various positions to increase TF activity of AR [55–59]. Ubiquitination, which increases proteasomal deg radation for the majority of proteins, plays a dual role in the case of AR. The ubiquitin ligase RNF6, which is upregulated in CRPC, acts not only to stimulate deg radation of AR, but also to increase its TF activity. A polyubiquitin chain attached to AR stimulates its complexation with chromatinassociated proteins and thereby facilitates its subsequent interaction with DNA of target genes [60]. On the other hand, activa tion of the E3 ubiquitin ligase CHIP (Cterminus of
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HSC70interacting protein)/STUB1 in response to 2methoxyestradiol arrests mitosis in PC cell lines [61]. Among proteins responsible for AR deubiquitina tion, Usp12 is considered as a potential target for CRPC therapy. Usp12 stabilizes AR by preventing its proteasomal degradation and modulating the PHLPP/PHLPPL–Akt–AR regulatory axis [62, 63]. Cofactors of the Androgen Receptor Changes in various cofactors affecting TF activity of AR provide an important mechanism of resistance to androgen deprivation. Once bound with its ligand, AR interacts with several proteins, including both corepressors and coactivators, prior to acting as a TF. The coactivators include various DNAbinding pro teins, TFs, and chromatin remodeling complexes. A role in carcinogenesis has been demonstrated for many of them; the proteins are involved in various pathways mediating higher cell proliferation and inva sion. The set includes the wellknown Her2/Neu epi dermal growth factor receptor, which indirectly stim ulates the AR binding to chromatin [64]; the Bcl2 apoptosis inhibitor [65]; the IGFBP5 insulinlike growth factor receptor [66]; and the ARbinding pro tein ARA70 [67]. Upregulation of these cofactors cor relates with the development of drug resistance in PC. Other oncogenic factors have been implicated in AR coactivation over the past years. The factors include the multifunctional DNA and RNAbinding protein FUS/TLS (fused/transloated in liposarcoma) [68]; KLF8 (Krüppellike factor 8) TF, which has zinc fin ger motifs [69]; and ORF1p, which is expressed from the L1 retrotransposon [70]. The coactivators can be considered as potential tar gets for CRPC therapy. Special attention is payed to the role the HSP27 chaperone plays in ADT resis tance. HSP27 is expressed to a low level in normal prostate cells and PC cells of ADTnaïve patients. However, HSP27 expression substantially increases 4 weeks after the ADT initiation and reaches a stably high level in androgenindependent tumors [71, 72]. Apart from its coactivator function, HSP27 is involved in the Stat3mediated block of apoptosis [72], the epi thelial–mesenchymal transition, and other carcino genesisrelated processes [73, 74]. HSP70 is promising as a therapeutic target. Several compounds have been proposed for inhibiting HSP27 expression. Of these, the antisense oligonucleotide OGX427 (Apatorsen) deserves special attention. Promising results have been obtained in Phase II clinical studies with OGX427 used to treat CRPC in patients after chemotherapy or after ADT only [75, 76]. An optimal therapeutic effect has been achieved with OGX427 used in combination with PF04929113, which acts as a Hsp90 chaperone inhibitor. A combination of the agents exerts a syner gic effect, leading to greater tumor growth suppression and higher cancer cell apoptosis rate [77].
Mutations and Overexpression of the Glucocorticoid Receptors Activation of the glucocorticoid receptor (GR) sig naling pathways provides a means to maintain cell proliferation in androgen deprivation. Inactive GR occurs in the cytoplasm. The interaction with a ligand, primarily cortisol, activates GR and causes its dimer ization. Active GR can remain in the cytoplasm and bind with other TFs, thus preventing their translocation into the nucleus. This is the case mostly with NFκB and AP1, which are responsible for expression of several proinflammatory genes [78]. Transactivation properties of GR play a primary role in CRPC. As with AR, the active GR dimer is transferred into the nucleus and triggers expression of its target genes, whose set overlaps with the set of AR targets. The GR target genes include those coding for proteins possessing antiapoptotic activity, such as glucocorticoid regulated kinase 1 (SGK1) and phos phatase DUSP1/MKP1 [79, 80]. Hyperactivation of the GR pathway is possibly one of the mechanisms responsible for resistance to AR inhibitors, including enzalutamide [81]. The androgendependent pathway plays a major role in regulating GR expression [82]. GR expression increases in androgen activity deficit associated with ADT. As has been observed in model systems, the GR level inversely correlates with expression of AR and the prostatespecific antigen (PSA), and the levels of these two proteins positively correlate with the tumor inva sion rate and the extent of metastasis [82]. The AR pathway is activated in CRPC resistant to androgen deprivation, while the GR level remains normal [82]. GR is considered as a therapeutic target in the case of tumors of other origins and histological types with a poor response to standard treatments, such as triple negative breast cancer [83]. Thus, a variety of mechanisms determine ADT resistance. One particular mechanism (e.g., AR splice variants or mutations or CUP17A1 overexpression) can be found to make the greatest contribution to tumor progression in the majority of cases, but there is always no certainty that the mechanism acts alone. Several mechanisms may act in one cancer cell to affect activation of the AR pathway, including AR mutations, AR phosphorylation, elevated expression of AR corepressors or coactivators, etc. When one resistance factor is eliminated, as is the case with abi raterone treatment to suppress the production of DHT precursors, cancer cells adapt to the change by sub stantially increasing the import of close DHT precur sors from the blood. CROSSRESISTANCE MECHANISMS Unfortunately, consecutive treatments with new antiCRPC drugs, such as abiraterone, enzalutamide, docetaxel, and cabazitaxel, have only a limited effi MOLECULAR BIOLOGY
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cacy. Data on crossresistance to these drugs are accu mulating [84, 85]. Although cabazitaxel is a new tax ane, studies have demonstrated a dramatic decrease in its efficacy in abirateronetreated patients and com plete lack of efficacy in patients with abiraterone resistant tumors [86]. Similar results have been obtained for the drugs used in the opposite order [84, 87, 88]. Marked crossresistance has been observed for enzalutamide, abiraterone, and docetaxel [89, 90]. While abiraterone acts mostly to suppress the pro duction of androgens necessary for AR activation and enzalutamide targets AR, the primary effect of doce taxel and cabazitaxel is suppressed microtubule depo lymerization. An impaired dynamics of microtubules prevents cell division. Thus, basically different mech anisms of action are characteristic of taxanes, abirater one, and enzalutamide, but common resistance mechanisms can be assumed for the drugs from clini cal study results. Crossresistance to drugs of different classes has been demonstrated with a cell line model [91]. PC346 cells were cultured in the presence of abiraterone for a long time and acquired resistance not only to abirater one, but also to docetaxel, cabazitaxel, and enzaluta mide. The drugs failed to prevent AR translocation into the nucleus. Similar results were obtained for cells grown in the presence of enzalutamide [91]. There is still no consensus as to what mechanisms sustain crossresistance to taxanes (docetaxel and cabazitaxel) and AR pathway inhibitors (enzalutamide and abiraterone) [92, 93]. Taxanes act mostly by impairing micrutubule depolymerization to prevent the cell cycle progress and to cause what is known as frozen mitosis. The mechanism of action of docetaxel in CRPC is thought to involve a block of AR translo cation into the nucleus as a consequence of an impaired microtubule dynamics [91], although no effect on intracellular AR transport has been observed for docetaxel in another study [94]. Still, therapy regimens based on consecutive treat ments with drugs of different classes are quite efficient in a certain proportion of cases (approximately 10– 30%) [87, 95]. A problem to solve in the nearest future is to identify markers of clinical efficacy of enzaluta mide administered after abiraterone treatment (and vice versa), in particular, in abirateronerefractory tumors [95, 96]. The best candidate markers for pre dicting the drug efficacy are now CYP17A1 overex pression in the case of abiraterone [97] and the absence of LBDlacking AR splice variants and lack of mutations in position 876 in the case of enzalutamide [98]. A prognostic significance is known for clinical characteristics, such as the PSA level, Gleason score, and time to tumor progression on treatment with drugs of other classes [99]. Thus, a contribution to drug resistance is made by various changes, such as mutations, splice variants, AR cofactors, increased DHT synthesis, and increased import of DHT precursors. Particular resistance MOLECULAR BIOLOGY
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mechanisms may prevail depending on the disease stage and treatments administered. Abiraterone resis tance is due to several factors: upregulation of genes involved in DHT synthesis and import of DHT steroid precursors, mutations that affect AR to extent the range of its ligands (H874Y, T877A, and T877S), and generation of constitutively active AR splice variants devoid of LBD. In the case of enzalutamide, AR splice variants and mutant forms (mostly F876L) play a main role in resistance. Simultaneous inhibition of several signaling path ways provides a means to overcome drug resistance. Recent studies with animal and cell models have shown that enzalutamide treatment combined with blocking the PI3K/Akt signaling pathway, which is activated in CRPC, produces impressive results [100, 101]. In particular, the Akt inhibitor AZD5363 stimu lates apoptosis and substantially inhibits cell prolifera tion in enzalutamideresistant cell cultures and tumors (both in vitro and in vivo) [100]. Experiments with animal models have shown that a combination of enzalutamide and AZD5363 causes tumor regression without any recurrence seen, while monotherapy with either drug inevitably leads to drug resistance [101]. The best results have been achieved upon early com bined treatment with enzalutamide and Akt inhibitors [101]. Thus, targets for CRPC therapy should not be restricted to components of the androgendependent signaling pathway. Positive results have been obtained by simultaneous inactivation of the AR and PI3K/Akt signaling pathways, as well as the pathways responsible for vascular endothelial growth (in particular, VEGFR and its regulator SRPK1) [102] or mediated by PLK1 [103], PKA [104], etc. The most promising current treatment is a combination of enzalutamide with the Akt inhibitors AZD5363 and AZD8186. CONCLUSIONS Several new drugs have recently been approved for CRPC treatment, including abiraterone (CYP17A1 inhibitor) and enzalutamide (a direct AR antagonist). The development of drug resistance during CRPC therapy is a central problem of modern urooncology. The mechanisms responsible for drug resistance can be divided into two groups (figure). Androgendependent mechanisms are: —AR overexpression, which is often due to chro mosome locus amplification; —upregulation of genes involved in various steps of DHT synthesis, providing for intratumoral production of androgens from their steroid precursors; —increased import of cholesterol or other steroid precursors; —mutations of androgen synthesis enzymes to abolish the inhibitory properties of abiraterone and other drugs;
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—upregulation of AR coactivators; —AR mutations that increase AR affinity for coac tivators; —AR posttranslational modification to increase AR transport into the nucleus; and —posttranslational modification of the Ntermi nal domain of AR to stabilize AR and to increase its activity. Androgenindependent mechanisms are: —expression of constitutively active AR variants devoid of the ligandbinding domain; —AR mutations that extend the range of AR ligands to include progestin, estradiol, and other ste roid hormones; and —hyperactivation of glucocorticoiddependent signaling pathways. A promising approach to CRPC therapy aimed at solving the problem of drug resistance is using a com bination of drugs to target several signaling pathways. A combination of enzalutamide with Akt inhibitors (AZD5363 and AZD8186) may come to be a new standard CRPC therapy in the nearest future. ACKNOWLEDGMENTS This work was performed using the equipment of EIMB RAS “Genome” center (http://www.eimb.ru/ RUSSIAN_NEW/INSTITUTE/ccu_genome_c.php) under the financial support by the Ministry of Edu cation and Science of the Russian Federation (Con tract no. 14.621.21.0001, project’s unique identifier RFMEFI62114X0001). REFERENCES 1. Karantanos T., Corn P.G., Thompson T.C. 2013. Pros tate cancer progression after androgen deprivation therapy: Mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 32, 5501–5511. 2. Wong Y.N., Ferraldeschi R., Attard G., de Bono J. 2014. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat. Rev. Clin. Oncol. 11, 365–376. 3. Zobniw C.M., Causebrook A., Fong M.K. 2014. Clin ical use of abiraterone in the treatment of metastatic castrationresistant prostate cancer. Res. Rep. Urol. 6, 97–105. 4. ElAmm J., Patel N., Freeman A., AragonChing J.B. 2013. Metastatic castrationresistant prostate cancer: Critical review of enzalutamide. Clin. Med. Insights Oncol. 7, 235–245. 5. Brasso K., Thomsen F.B., Schrader A.J., Schmid S.C., Lorente D., Retz M., Merseburger A.S., von Klot C.A., Boegemann M., de Bono J. 2014. Enzalutamide anti tumour activity against metastatic castrationresistant prostate cancer previously treated with docetaxel and abi raterone: A multicentre analysis. Eur. Urol. pii S0302 2838(14)006800; doi 10.1016/j.eururo.2014.07.028
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Translated by T. Tkacheva
MOLECULAR BIOLOGY
Vol. 49
No. 5
2015