The hallmarks of castration-resistant prostate cancers

Cancer Treatment Reviews xxx (2015) xxx–xxx

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Tumour Review

The hallmarks of castration-resistant prostate cancers Maria Katsogiannou ⇑,1, Hajer Ziouziou 1, Sara Karaki, Claudia Andrieu, Marie Henry de Villeneuve, Palma Rocchi ⇑ Inserm, UMR1068, CRCM, Marseille F-13009, France Institut Paoli-Calmettes, Marseille F-13009, France Aix-Marseille Université, F-13284 Marseille, France CNRS, UMR7258, CRCM, Marseille F-13009, France

a r t i c l e

i n f o

Article history: Received 11 February 2015 Received in revised form 30 April 2015 Accepted 4 May 2015 Available online xxxx Keywords: Castration resistant mechanisms Prostate cancer Hallmarks Androgen receptor

a b s t r a c t Prostate cancer has become a real public health issue in industrialized countries, mainly due to patients’ relapse by castration-refractory disease after androgen ablation. Castration-resistant prostate cancer is an incurable and highly aggressive terminal stage of prostate cancer, seriously jeopardizing the patient’s quality of life and lifespan. The management of castration-resistant prostate cancer is complex and has opened new fields of research during the last decade leading to an improved understanding of the biology of the disease and the development of new therapies. Most advanced tumors resistant to therapy still maintain the androgen receptor-pathway, which plays a central role for survival and growth of most castration-resistant prostate cancers. Many mechanisms induce the emergence of the castration resistant phenotype through this pathway. However some non-related AR pathways like neuroendocrine cells or overexpression of anti-apoptotic proteins like Hsp27 are described to be involved in CRPC progression. More recently, loss of expression of tumor suppressor gene, post-transcriptional modification using miRNA, epigenetic alterations, alternatif splicing and gene fusion became also hallmarks of castration-resistant prostate cancer. This review presents an up-to-date overview of the androgen receptor-related mechanisms as well as the latest evidence of the non-AR-related mechanisms underlying castration-resistant prostate cancer progression. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Prostate cancer (PC) is the second leading cause of cancer-related death in men in the western world after lung cancer [1,2]. According to the American Cancer Society estimates in 2013, over 230,000 American men will be diagnosed with prostate cancer and nearly 29,720 will die of the disease [2]. PC progresses from diagnosis to death through a series of clinical states characterized by the extent of the disease, the hormonal status (castrate or non-castrate) and the presence or absence of metastases. Before choosing a PC treatment, some parameters are considered for each patient such as age, health, stage and grade of the disease, PSA level. . .etc. Treatments can be applied as mono- or combined ⇑ Corresponding authors at: Aix-Marseille Université, U105, F-13284 Marseille, France. Tel.: +33 486 977 266; fax: +33 486 977 499 (M. Katsogiannou). Tel.: +33 486977267; fax: +33 486977499 (P. Rocchi). E-mail addresses: [email protected] (M. Katsogiannou), palma. [email protected] (P. Rocchi). 1 Both authors contributed equally to this work.

therapies. Common options for PC treatments include: active surveillance, surgery (prostatectomy), radiation therapy, chemotherapy or hormone-therapy (androgen deprivation therapy ADT). Active surveillance is often used when an early stage, slow-growing PC is found in older men. It may also be suggested when the risks of surgery, radiation therapy, or hormonal-therapy outweigh the possible benefits. Most patients initially respond well to androgen deprivation (ADT) leading to disease regression. Unfortunately, PC will ultimately become unresponsive and recur within 1–3 years after ADT as a castration-resistant prostate cancer (CRPC) [3]. CRPC is an incurable and highly aggressive terminal stage of PC, seriously jeopardizing the patient’s quality of life and lifespan. The management of CRPC is complex and has opened new fields of research during the last decade leading to an improved understanding of the biology of the disease and the development of new therapies [4–7]. This review presents an up-to-date overview of the androgen receptor (AR)-related mechanisms as well as the latest evidence of the non-AR-related mechanisms underlying CRPC progression.

http://dx.doi.org/10.1016/j.ctrv.2015.05.003 0305-7372/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Katsogiannou M et al. The hallmarks of castration-resistant prostate cancers. Cancer Treat Rev (2015), http://dx.doi.org/ 10.1016/j.ctrv.2015.05.003

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From castration-sensitivity to castration-resistance Growth of the prostate gland is initially dependent on androgens. Under constant stimulation by androgens, the prostate gland gradually develops into PC, which is the rationale for androgen deprivation therapy (ADT). Tumors that relapse CT were first thought to be ‘‘an drogen-independent’’, but very low levels of androgens may still be detectable in the tissues and serum of advanced patients [8,9]. ADT provides selective pressure leading to outgrowths of CR cancers [10]. Most advanced tumors resistant to CT still maintain expression of a functional AR showing that the AR pathway plays a central role for survival and growth of most CRPC [11–15] and constitutes an attractive target for therapy. Hence, how AR promotes cell proliferation and tumor growth is an extensive area of research and several mechanisms induce the emergence of the castration resistant phenotype [16]. In addition to AR-related-pathways, more and more non-AR-related pathways like anti-apoptotic proteins overexpression, mRNA splicing events, gene fusions loss of expression of tumor suppressor gene, post-transcriptional modification using miRNA, epigenetic alterations, have also become the new hallmarks of CRPC. PC growth and progression are driven by the accumulation of genetic and epigenetic alterations, events that will be reviewed here. Discovery and understanding of these mechanisms has led to the development of new generation of therapies for the treatment of CRPC [17]. Thus, 6 novel therapies have been approved by the Food and Drug Administration (FDA) for the treatment of CRPC in just the last few years (sipuleucel-T, cabazitaxel, denosumab, abiraterone, enzalutamide and Ra-223) and a few others demonstrating promising results in late-phase clinical trials (for review [4,6,7]). AR-related pathways Hypersensitive pathway AR could become sensitive to low amounts of residual androgens through increased protein production. This theory of a hypersensitive AR pathway (Fig. 1, pathway A) is supported by the fact that many CR tumors show overproduction of AR resulting of a selective outgrowth following death of cells during CT [13,18,19]. Excess of AR production could result from AR locus amplification, increased mRNA transcription rates and/or stabilization of the mRNA or protein [20,21]. Regardless of the mechanism, AR overproduction is expected to contribute to PC growth by compensating for low androgens levels after ADT. Among latest therapeutic strategies developed and FDA-approved, Enzalutamide is a novel antiandrogen selected for novel clinical development with promising results [22], presenting great affinity for the AR, lacks agonists effects and inhibits not only ligand binding to the receptor in a competitive manner but also AR nuclear translocation and DNA fixation. Clinical results showed a slowing down in cancer cell growth, induction of cancer cell apoptosis and tumor regression [23]. Intracrine androgen metabolism PC cells may survive ADT by regulating intracrine androgen synthesis within the prostate (Fig. 1, pathway B). This local synthesis of androgens is due to increased testosterone conversion to DHT resulting from overproduction of the 5a-reductase enzyme [24,25]. Increased 5a-reductase enzyme level results itself from a germline variant substituting valine to leucine at codon 89 [26]. This variant is commonly observed in African men, indicating a genetic influence in PC [13,19,27]. Intraprostatic androgens can also be synthesized from cholesterol or other precursors such as DHEA (dehydroepiandrosterone). DHEA could be converted to androstenedione, a substrate for conversion to testosterone. The expression of all the genes necessary for synthesizing androgens

are described to be increased in CRPC compared to early PC analyzed from untreated patients [9,25,28,29]. Among the recently developed drugs, abiraterone acetate is an inhibitor of CYP17A, an enzyme involved in the intratumoral androgen biosynthesis. Abiraterone has been shown to be effective and very potent and represents the first hormonal therapy to be approved in the post-chemotherapy setting for CRPC [4,6]. Promiscuous pathway The promiscuous pathway results in the AR being receptive to ligands other than DHT (Fig. 1, pathway C/D). AR mutations enhance AR ligand binding specificity [30–32] and its activation by weak adrenal androgens and other steroid hormones including DHEA, progesterone, estrogens and cortisol [33–37]. AR substitutions are referenced in a database (http://androgendb.mcgill.ca/). These mutations have various consequences depending on their localization [33,38,39]. For instance, cells from the LNCaP (castration-sensitive) cell line display an AR missense mutation in the ligand-binding domain. At codon 877, the threonine is substituted to alanine, which opens the AR sensitivity to a wide range of steroid ligands [40,41]. This mutation may also convert AR antagonists (flutamide and bicalutamide) to AR agonists. AR antagonist treatments may in fact select tumors expressing AR mutants activated by the therapeutic agents [42]. Other mutations, which occur in the AR DNA-binding domain or in the N-terminal domain, modulate the binding specificity of its co-regulators and the transcriptional activation of its target genes [43–45]. Interestingly, two mutations (T877A and Q640X) constitutively activate AR [46]. Finally, AR splice variants (AR3, 4 and 5), which have lost their C-terminal protein domain (ligand-binding domain) including the canonical nuclear localization signal (NLS), can activate AR target genes [47–51]. Mutants truncated in the N-terminal domain (DNA-binding domain) are still able to translocate into the nucleus and have ligand-independent transcriptional activity. Importantly, the expression of certain AR variants such as AR-V7 is associated with a short time to disease recurrence following radical prostatectomy [48,50,52]. These AR variants are key mediators of persistent AR signaling and androgen withdrawal therapies [53]. They represent a clinical challenge depending on their sensitivity to AR antagonists designed to target the AR ligand-binding domain. A small molecule (EPI-001) targeting the AR N-terminal domain has been recently designed and its efficiency against tumors expressing AR splice variants is under study [54]. Numerous pre-clinical studies show the efficiency of AR-siRNA strategy in inducing CR tumor growth inhibition and regression [55,56]. Outlaw pathway The outlaw pathway (Fig. 1, pathway E) is functional when the AR pathway is activated by growth factors, cytokines and receptor tyrosine kinases. Growth factor pathways such as IGF1 (insulin-like growth factor) and EGF (epidermal growth factor) can bind and activate AR in the castrated state, when they are overexpressed [57]. IGF1 has been also described to be involved in CR evolution in an AR-independent fashion. IGF1 promotes cell growth, survival and differentiation of prostate cells and is increased in advanced cancers especially in metastases [58]. IGF1 can activate powerful oncogenic signaling pathways such as RAS, RAF, MAPK, or PKC leading to the transcription of target genes that promote cell growth and survival [59]. Cytokines like interleukin-6 (IL6) and interleukin-4 (IL4) are also activators of the AR pathway in CRPC [60,61]. Notably, IL6 could activate AR through the activation of MAPK (mitogen-activated protein kinase) and STAT3 pathways [62]. Moreover, tyrosine kinase receptors such as ERBB2 are overexpressed in CRPC, resulting in the increase of AR expression and activity via the activation of

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A. Amplification and hypersensibility of AR Low levels of T

C. Mutations of AR Steroïdes non A: Cortison, Oestradiol…

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Fig. 1. Androgen receptor (AR)-related and alternative pathways contributing to castration-resistant emergence and progression on prostate cancer.

MAPK and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways [63–66]. The PI3K/AKT pathway seems required for AR protein expression because AKT mutant or PI3K disruption reduce AR protein level [65]. These kinase pathways enhance AR activity indirectly by mediating the phosphorylation of co-activators rather than directly mediating the phosphorylation of AR itself [67]. Finally, a cross-talk between NF-jB and AR indicates the role of the NF-jB signaling pathway in CR progression [68]. Phase II clinical trials of mTOR inhibitors (ridaforolimus, temsirolimus and everolimus), targeting the PI3K pathway in CRPC have not been overwhelming [69– 71]. Nevertheless, combinatory trials of PI3K and AR inhibition have

shown more promising results but may encounter some toxicity issues [72]. Alterations in co-factors recruitment Co-activator levels are increased in CR cancers enhancing the sensitivity of AR to various ligands other than androgens (Fig. 1, pathway F). Co-activators such as ARA70, ARA55, SRC-1, P/CAF and GRIP1/TIF2 are overexpressed in PC [13,73–77]. Additionally, loss of AR co-repressor function may promote AR transcription activity in CRPC such as the exclusion of NCoR from the AR

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complex. Recently, nucleophosmin (NPM/B23), a member of the histone chaperone family, has also been identified as an AR co-factor. NPM binds to AR and enhances AR binding to its binding sites (AREs) [78]. Because NPM stimulates histone acetyltransferase p300, it is suggested that NPM facilitates AR attachment to DNA via p300 action on the chromatin [79]. Hence, NPM enhances AR transcriptional activity and the relationship between these two proteins may play a crucial role in PC progression. Together, in a low-hormone environment, the gain of co-activators and loss of co-repressors provide a compensatory mechanism for CR tumors. Recently, potent inhibitors of AR Binding factor 3 (BF3) pocket were developed, specifically targeting the interaction with AR and show activity in enzalutamide-resistant preclinical models [80]. Moreover, a novel class of small molecules has been recently developed (LXXLL peptidomimetics) and constitutes promising candidates for clinical development, has shown to disrupt AR co-activator interactions [81]. Neuroendocrine cells Neuroendocrine cells are a minor cell population of the epithelial compartment of normal prostate glands (Fig. 1, pathway G). In PC, neuroendocrine cells could be well-represented in CR tumors because they resist to ADT due to their lack of AR expression. The neuroendocrine phenotype acquisition is associated with tumor progression and castration resistance. Increasing evidence shows that neuroendocrine IL6 factor, one crucial factor induced by castration, enhances the neuroendocrine phenotype, thereby amplifying the wave of survival factor release [60,82]. Neuroendocrine cells notably secrete neuropeptides (NPs) such as bombesin/Gastrin-Releasing Peptide (GRP) or adrenomedullin described to induce paracrine mitogenic effects on PC cells via AR pathway activation [83–86]. Furthermore, neuroendocrine cells could promote the growth of CS tumors in castrated mice even when injected into the opposing flank, suggesting a paracrine and endocrine mechanism [87]. Data support the up-regulation of the neuroendocrine pathway after AR suppression [88,89] but the precise role of neuroendocrine cells is still unclear as their precise role in CR progression still unknown. Accumulating data support the existence of predisposing aberrations in neuroendocrine prostate cancer (NEPC) including loss of RB1 and TP53 and gain of MYCN and AURKA (for review see [17]). AURKA inhibitor MLN8237 was used in phase II trial in NEPC (NCT01799278). Non-AR-related pathways Anti-apoptotic proteins overexpression Anti-apoptotic proteins overexpression circumvents the AR pathway and utilizes other pathways to stimulate prostate cells proliferation in a CR environment (Fig. 1, pathway H). CR progression is associated with activation of anti-apoptotic proteins such as BCL2 [90–92] and clusterin [93]. We previously described that Hsp27 [94,95] and TP53INP1 [96] are upregulated in CRPC and block apoptosis normally induced by androgen withdrawal and chemotherapies. Notably, Hsp27 belongs to the 1% of genes overexpressed during CR progression [94,95] and is associated with poor prognosis and treatment resistance [97]. We also recently demonstrated that Hsp27 is a multifunctional protein capable of interacting with a great number of partner proteins to protect cells from lethal conditions [98]. We showed that the Hsp27-interacting protein TCTP is involved in Hsp27 cytoprotection in CRPC [99]. Hsp27 stabilizes TCTP by inhibiting its stress-induced ubiquitination and proteasomal degradation [99]. We provided proof-of-principle that TCTP is an inhibitor of apoptosis in human CRPC, and a rational target for therapy of CRPC that could avoid

undesirable toxicity in normal tissues through TCTP inhibition (antisense oligonucleotide) [99,100]. Hsp27 cytoprotection is also induced through its interaction with eIF4E (eukaryotic translational initiation factor 4E). Hsp27 interaction protects eIF4E from its ubiquitin–proteasome-dependent degradation process, leading to apoptosis resistance induced by castration and chemotherapy [101]. In this context, two inhibitors for anti-apoptotic proteins Hsp27 and clusterin have been developed (OGX-427 and OGX-011 respectively) and are currently used in clinical phases II and III (http://clinicaltrials.gov/). Tumor suppressor deregulation PTEN deregulation in PC initiation and progression have been largely described, nevertheless, a role for the retinoblastoma (RB1) and P53 tumor suppressors (Fig. 1, pathway I). The tumor suppressor PTEN is inactivated in CRPC by genetic mutations [102,103]. PTEN expression is often lost and reduced in advanced metastatic tumors compared to primary tumors [102]. PTEN loss causes aberrant activation of the PI3K/AKT signaling pathway, which increases AR protein level and transcriptional activity. In PTEN-deleted PC tumors, mTORC2 (mammalian target of rapamycin complex 2) is required to phosphorylate AKT at another site [104]. Loss of the PTEN regulatory phosphatase activity results in AKT recruitment and activation. In addition to influencing AR activity, activated AKT has a number of AR-independent downstream effects such as apoptosis blockage, cell proliferation and protein synthesis/cell growth [105]. AKT prevents cells from apoptosis by phosphorylating and inactivating pro-apoptotic proteins BAD and pro-caspase 9 [64] and promotes cell growth by downregulating the cell cycle inhibitor P27 [106–108]. The transcription factor and AKT target fork-head box O1 (FOXO1) induces the transcription of target genes that induce apoptosis. AKT phosphorylation of FOXO1 excludes it from the nucleus preventing cell death [109]. Functional inactivation or loss of the RB1 tumor suppressor is frequent in CRPC. RB1 loss results in upregulation of AR protein level and aberrant AR-mediated gene transcription activity. Hence, RB1 downregulation contributes to CR progression and DNA damage checkpoints loss. P53 mutations or loss are commonly found in advanced PC and bone metastasis but are uncommon in primary PC [110–112]. Thus, P53 is thought to play a role in PC progression but the extent of its contribution is still unclear. Burchardt et al. were the first to suggest that P53 mutations may promote CRPC progression [113]. P53 inhibition or loss-of-function conferred to in castration-sensitive (CS) LNCaP cells but not to parental LNCaP cells the ability to form tumors in castrated male nude mice. Recent studies have suggested that wild-type P53 is necessary for AR signaling [114] and that P53 is required for stable binding of AR to certain chromatin regions. Furthermore, it has been reported that P53 elimination in CS cells leads to cell proliferation independently of androgens [115]. Interestingly, we previously demonstrated that CRPC progression correlates with translationally controlled tumor protein (TCTP) overexpression and loss of P53. TCTP knockdown restored P53 expression and function, suggesting that castration-sensitivity is directly linked to P53 expression [116]. Taken together, these recent data show the importance of RB1 and P53 loss of functions in the transition of CSPC to CRPC and provide new insights for the development of predictive markers of response to ADT that might guide therapeutic decisions. In addition to mutations of P53, PTEN, mutations have been described in ZFHX3, RB1, APC, OR5L1, CDK12 and MLL2 [117]. miRNAs MicroRNAs (miRNAs) are non-coding RNAs that can repress protein expression by inhibiting their translation or promoting

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mRNA degradation by base-pairing interactions with the 30 -UTR. MiRNAs may play the role of broad-spectrum oncogenes (oncomirs) or tumor suppressors (anti-oncomirs) [118] (Fig. 1, pathway J and Fig. 2). Hence, their use as prognostic, diagnostic or therapeutic biomolecules is under study [119]. Many studies have defined miRNAs with oncogenic properties in CR progression [120]. For instance, miR-221/222 upregulation has been described in CRPC [118] and an inverse correlation between miRNA-221/222 expression [121] and P27 has been reported [121,122]. On the contrary, miRNA-15a/16 is downregulated in PC samples and it has been further suggested that, because miRNA-15a/miRNA-16 are able to post-transcriptionally repress the expression of BCL2 and WNT3A, their reduced levels may play an essential role in CRPC. BCL2 upregulation is a common event in CR progression that promotes cell survival after androgens deprivation [90,92]. WNT3A has been implicated in b-catenin stabilization, which acts as a co-activator of AR promoting its activity in the presence of low androgen levels and in AKT and MAPK, activation which also provide PC cell survival and proliferation in the absence of androgens [123]. Thus, several lines of evidence support the fact that miRNA-15a/16 loss contribute to CR progression. Finally, another interesting miRNA suggested to be involved in CRPC progression is miRNA-34. Recent studies have implicated miRNA-34 in the P53 network [124,125]. miRNA-34 expression is markedly induced in a P53-dependent manner and its activation results in cell cycle arrest and apoptosis through downregulation of proteins such as cyclin D1 or BCL2 [126]. Interestingly, miRNA-34 has been found to be absent in P53-defective CRPC PC-3 and DU-145 cells [118]. These observations suggest that the loss of miRNA-34 promotes CR progression by activating proteins that enhance cell proliferation and inhibit apoptosis. Therefore, miRNA-34 is implicated in a positive feedback loop with P53 and its loss recapitulates, at least in part, P53 loss-of-function. Interestingly, several miRNAs (miR-21, miR-141, miR-221/222 and many others) have been described to regulate AR or to be regulated by AR and then to affect various signaling pathways related to cellular functions and tumor processes (cell proliferation, cell cycle transition, apoptosis, angiogenesis, castration invasion and metastasis) [120]. Among them oncomirs are highly expressed in CRPC, while anti-oncomirs are underexpressed (Fig. 2). miRNA-based therapeutics (miRNA antagonists (siRNA) and miRNA mimics) are being rapidly developed and are in phase II clinical trials in the case of Hepatitis C virus. In prostate cancer, systemic delivery of miR-34 mimic blocked tumor growth in mouse models [127].

Epigenetic changes Alterations in chromatin structure are tightly related to changes in gene transcription (Fig. 1, pathway K). DNA and histone

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modifications like methylation or acetylation are critical regulators of gene expression. DNA methylation is mediated by DNA methyltransferases that methylate cytosine residues. 80–90% of coding CpG (50 -cytosine phosphatase guanidine-30 ) dinucleotides are methylated. CpG hypermethylation in human gene promoters is associated with gene silencing while hypomethylation results in increased gene transcription [128]. Increasing evidence have suggested that aberrant DNA methylation resulting in gene expression alterations may contribute to CR progression by promoting genomic instability [129]. As described above, PTEN loss-of-function plays an important role in CR progression and PTEN silencing is often the consequence of CpG islands methylation located in its promoter region [102,130]. This aberrant PTEN promoter region methylation would have a role in CR progression via the loss of PTEN and the activation of PI3K/AKT signaling pathway. In 30% of CRPC, the AR promoter region is hypermethylated, resulting in the loss of AR expression in those tumors [131]. A recent study has used metastatic CRPC tumors obtained at autopsy to identify the most common gene copy number aberrations and their concordant methylation levels in metastatic CRPC [132]. Gene copy number and CpG methylation was found to work in concert, particularly for genes commonly deleted in CRPC and that this cooperation seems to be essential for inhibiting the expression of critical tumor suppressors like RB1. Thus, DNA methylation seems to be a key epigenetic change that contributes to CR progression, highlighting the possibility of targeting such alterations in CRPC. Hypomethylating agents (e.g. 5-azacytidine) are already available and their efficiency to delay the progression of CR disease is under pre-clinical study [132].

Alternative splicing Splicing events control gene expression and their alteration plays a role in human disease and cancer [133]. The spliceosome complex is characterized by a dynamic composition and conformation. It results from the ordered interactions of small nuclear ribonucleoprotein (snRNPs) and numerous splicing factors [134]. mRNA alternative splicing (AS) (Fig. 1, pathway L) is a gene-expression regulation strategy used by cells to increase protein variety and regulation. Modulation of protein functions by AS has been documented for several genes in PC including AR itself, indicating that this mechanism can significantly contribute to genotypic heterogeneity in cancer cells and among CRPC patients [135,136]. Growing evidence show that AS of AR is a key capability of cancer cells to evade the normal activation of the pathway [136]. Splicing is itself controlled by several mechanisms. Our discovery of direct interactions of Hsp27 with splicing factors, regulators and spliceosome ribonucleoproteins as well as experimental evidence for the alternative splicing of 1777 genes in PC cells in the

CRPC progression Oncomirs miR-221/222/P27/AR miR-221/222/ /P27 27/A / R miR-21/AR miR-141/AR

An-oncomirs miRNA-34/Cyclin miRNA-34/C /Cyclililin D1/BCL2/P53 /C D1/BC /BCLL2/P53 miRNA-15a/16/P53/BCL2/WNT3A Fig. 2. Oncomirs are highly expressed in castration resistant prostate cancer and anti-oncomirs are underexpressed. miRNAs are in black and their target proteins in red.

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absence of Hsp27, strongly supports the involvement of Hsp27 in differential splicing events [98]. High-throughput analyses of PC samples have revealed more than 200 genes whose AS is differentially regulated. The physiological consequence of the majority of these aberrant AS events is still unknown [137]. Two critical pathways in CRPC are subject to AS control, AR and PI3K/AKT/mTOR [138]. The majority of the alternatively spliced genes show a variation in the expression levels, the best known examples including AR, transcription factor KLF6 (Kruppel-like factor 6), cyclin D1 (CCDN1), BCL-X, FGFR2 and VEGFA (Fig. 3). Several studies suggest that the upregulation of selected splicing factors (SAM68, SRSF1, DDX5) directly alter the splicing profile of key genes [135,138] and therefore constitute potential therapeutic targets. However, inhibition of a splicing factor activity is not an easy task, despite some examples of success [139]. Spliceostatin A (SSA), targeting the splicing factor 3B subunit 1 (SF3B1) shows anti-oncogenic properties in a variety of cancer cell models [140]. Altogether, AS (de)regulation represents a relatively unexplored aspect of the of CRPC complexity that deserve further exploration. Furthermore, clinical investigation of applying antisense oligonucleotides to down-regulate mRNAs contributing to cancer cell survival has shown promising results [141] but no other therapeutic strategy has been proposed to date to target splicing.

Gene fusions Technological progress, notably the development of paired-end and whole transcriptome sequencing, or exon arrays, has allowed

CCND1 normal

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the discovery of an increasing number of chimeric RNAs in PC [142–145] (Fig. 1, pathway M). One of the earliest genetic alterations described to occur in 50% of PC but have also been observed in CR and metastatic PC [144,146], is the overexpression of the ERG oncogene, a member of the large family of ETS transcription factors involved in various biological processes such as cell proliferation, differentiation, apoptosis, metastasis and angiogenesis [147–149]. Because ERG fusion transcripts are so frequently observed in prostate tumors, their presence in tissue or urine represent potent diagnostic markers in a large group of patients. This deregulation results from the fusion of the ERG gene with the first exon(s) of transmembrane protease serine 2 (TMPRSS2), a prostate-specific and androgen-regulated gene located close to ERG (Fig. 4) on the same 21q22 chromosome region [147,150]. Fusion of these genes can occur either by interstitial deletion leading to loss of genomic region between the two genes (60% of fusion-positive tumors), or by complex genomic rearrangements involving various chromosomes [148]. This gene fusion is specific to PC as has never been detected in normal prostate [151,152]. It is frequently correlated with poor clinical outcome [153]. Interestingly, the AR has been implicated in the processes resulting in gene fusions by inducing the spatial proximity of genes involved in rearrangements, promoting the formation of double-strand DNA breaks (DSB), and facilitating the recruitment of proteins for non-homologous end-joining (NHEJ). Under androgens influence, changes in chromatin organization are induced that can juxtapose the transcription units of both genes, thereby facilitating the genesis of this gene fusion [154]. Interestingly, the presence of TMPRSS2-ERG

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Fig. 3. Alternative splicing leading to isoforms differentially regulated in prostate cancer (pink = up-regulated, green = down-regulated).

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ERG TMPRRS2

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Prostate cancer

Fig. 4. Gene fusion events are recurrent in castration-resistant prostate cancer. TMPRSS2-ERG fusion results in the upregulation of ERG transcription which then exerts its effects by binding target gene promoter regions, which results in their activation or inhibition, and the generation of neoplastic phenotype.

fusion was proposed as a biomarker for the identification of abiraterone-sensitive tumors [6]. ETS genes are frequently involved in gene fusions, resulting in the formation of chimeric proteins or altered expression of ETS proteins. Less frequently, ERG overexpression is not caused by TMPRSS2 fusion, but by fusion to SLC45A3 or NDRG1, both androgen-regulated genes preferentially expressed in prostate but not located on the same chromosomes ERG. This indicates that chromosomal proximity is not essential for fusion events but long distance gene fusions seem to be facilitated by nuclear proximity of the fusion partners [155,156]. In a small percentage (6%) of prostate tumors, the ETS gene ELK4 is deregulated due to cis-splicing of the adjacent SLC45A3 gene and with no apparent chromosomal rearrangement [157,158]. Moreover, it has been shown that TMPRSS2-ETS rearrangements also occur in CRPC providing strong evidence that ERG fusions represent an aggressive molecular subtype of PC suggesting the existence of castration-resistant mechanisms of TMPRSS2 expression in prostate [159,160]. In CRPC, one function of TMPRSS2-ERG is proposed to be the expansion of self-renewing cells, which may serve as targets for subsequent mutations [161]. The precise functional role of ERG and other ETS proteins in CRPC is not fully understood, because ETS overexpression alone is insufficient to induce PC. Some pathways associated to ERG overexpression have been identified, such as the TGFb, TDRD1 and WNT pathways [162–165]. Gene fusions in CRPC demand further investigation in order to decipher the role and outcome of gene fusions at this stage of the disease. Interestingly, patients with CRPC will be stratified for the presence of TMPRSS2-ERG fusion and randomized to abiraterone protocols (see clinicaltrials.gov, identifier: NCT01576172). A recent clinical trial using ABT-888 (Veliparib), an oral PARP inhibitor targeting TMPRSS2-ERG fusions has recently been carried out (see clinicaltrials.gov, identifier: NCT01085422, NCT01576172). Numerous studies show that PARP inhibitors, when added to hormone therapy, contribute to tumor regression especially those expressing TMPRSS2-ERG and clinical trials with several PARP inhibitors are currently being conducted in various cancers to assess their toxicities, efficacies and benefit as monotherapies or combined with radiation or other chemotherapeutic agents [166,167].

Conclusion and future directions Mechanisms underlying CRPC progression have been identified as early as the 1940s and many probably remain to be uncovered to fully understand the disease. Among the mechanisms, recent studies have identified a wide variety of recurrent mutations in proteins interacting with AR [117]. Due to the increasing amount of knowledge of the mutational profile of PC, there is a need to further understand the consequences of these recurrent mutations in CRPC progression. While there have been significant efforts to help understand CRPC biology over the past decades, some aspects of

genetic and epigenetic alterations deserve deeper exploration, such as alternative splicing, chimeric transcripts, miRNA interactions with target genes. Current knowledge of CRPC mechanisms have contributed to the development and FDA approval of various molecules which have allowed overall survival gains that were inevitably countered by resistance and emergence of a more aggressive and heterogeneous disease. We believe that further elucidation of CRPC mechanisms will increase the chances of finding new targets and designing new therapeutic options for CRPC, mainly cancer-specific combinatory therapies as well as siRNA and ASO therapeutic strategies as treatment alternatives. Translational research and close collaboration between physicians and researchers is indispensable for therapeutic strategies for this highly heterogeneous disease. Knowing a patient’s genetic and biological background of their tumor will be useful for identification of more effective prevention, screening and treatment strategies with fewer side effects allowing to customize and personalize therapy to each patient. In the future, optimal therapeutic choices will rely on targeting pathway combinations with the AR specific to patient sub-groups. Conflict of interest statement The authors declare they have no competing interests as defined by Nature Publishing Group, or other interests that might be perceived to influence the interpretation of the article. Acknowledgements The authors received financial support from: French Cancer Institute (InCa, PAIR prostate program #R10111AA), ITMO Cancer (BioSys call, #A12171AS), Institut national de la santé et de la recherche médicale (Inserm), Association pour la Recherche sur le Cancer (ARC), Agence Nationale pour la Recherche (ANR, Emergence Program #ANR-11-EMMA-0022), Aix-Marseille University and competitivity pole Eurobiomed, ARTP (Association pour la Recherche sur les Tumeurs de la Prostate, N° R14107AA). References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. [2] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11–30. [3] Fusi A, Procopio G, Della Torre S, Ricotta R, Bianchini G, Salvioni R, et al. Treatment options in hormone-refractory metastatic prostate carcinoma. Tumori 2004;90:535–46. [4] Galsky MD, Small AC, Tsao CK, Oh WK. Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes. CA Cancer J Clin 2012;62:299–308. [5] Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015;520:353–7. [6] Suzman DL, Antonarakis ES. Castration-resistant prostate cancer: latest evidence and therapeutic implications. Ther Adv Med Oncol 2014;6:167–79.

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Please cite this article in press as: Katsogiannou M et al. The hallmarks of castration-resistant prostate cancers. Cancer Treat Rev (2015), http://dx.doi.org/ 10.1016/j.ctrv.2015.05.003