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C-terminally truncated constitutively active androgen receptor variants and their biologic and clinical significance in castration-resistant prostate cancer

The Journal of Steroid Biochemistry and Molecular Biology, In Press, Corrected Proof, Available online 21 June 2016, Available online 21 June 2016


  • ARΔLBDs are products of alternative splicing (AR-V), premature stop codons (Q641X) or enzymatic cleavage (tr-AR).
  • ARΔLBDs can be subdivided into two structurally and functionally distinct subgroups, depending on the presence/absence of a hinge region.
  • Various ARΔLBDs are involved in PCa progression (castration resistance, EMT, glutaminolysis etc).
  • ARΔLBDs like AR-V7 are highly interesting new prognostic and therapeutic targets.


A mechanism allowing castration resistant prostate cancer cells to escape the effects of conventional anti-hormonal treatments is the synthesis of constitutively active, C-terminally truncated androgen receptor (AR)-variants. Lacking the entire or vast parts of the ligand binding domain, the intended target of traditional endocrine therapies, these AR-variants (termed ARΔLBD) are insensitive to all traditional treatments including second generation compounds like abiraterone, enzalutamide or ARN-509. Although ARΔLBD are predominantly products of alternative splicing, they can also be products of nonsense mutations or proteolytic cleavage. In this review, we will discuss the etiology and function of c-terminally truncated AR-variants and their clinical significance as markers/targets for the treatment of castration resistant prostate cancer.

Abbreviations: aa - amino-acids, ADT - androgen deprivation therapy, AR - androgen receptor, ARΔLBD - androgen receptor lacking a functional ligand binding domain, AR-V - AR splice variant, BET - bromodomain and extra-terminal, CE - cryptic exon, CRPC - castration-resistant prostate cancer, CTC - circulating tumor cell, CTD - carboxy-terminal domain, DBD - DNA-binding domain, EMT - epithelial-mesenchymal transition, FFPE - formalin-fixed paraffin-embedded, HR - hinge region, I - intron, IF - immunofluorescence, IGF-1 - insulin-like growth factor 1, IGF-1R - IGF-1 receptor, IHC - immunohistochemistry, LBD - ligand binding domain, TAD - transactivation domain, mCPRC - metastatic CPRC, MBD - microtubule binding domain, NES - nuclear export signal, NLS - nuclear localization signal, NTD - amino-terminal domain, PSA - prostate specific antigen, PCa - prostate cancer, qRT-PCR - quantitative reverse transcription polymerase chain reaction, RISH - RNA in situ hybridization, RNAseq - RNA sequencing, TAD - transactivation domain, tr-AR - truncated androgen receptor, U - unique c-terminal end, Z - zinc finger.

Keywords: Prostate cancer, Androgen receptor splice variants, Marker, Therapies.

1. Introduction

The androgen/androgen receptor(AR)-signaling axis plays a pivotal role in the development and growth of prostate cancer (PCa) cells. While treatment of organ confined PCa involves radical prostatectomy or radiation therapy, current treatment for advanced PCa is mainly based on androgen deprivation therapy (ADT) like surgical/chemical castration and/or application of anti-androgens. Although ADT is initially very effective, it is mainly palliative as PCa almost invariably progresses to a more aggressive and often lethal phenotype within 12–48 months of treatment in the metastatic setting [1]. This stage of the disease, termed metastatic castration-resistant prostate cancer (mCRPC) is characterized by sustained AR-signaling despite anorchid levels of circulating androgens. The mechanisms leading to castration resistance include overexpression of full length AR-protein, gain of function mutations broadening AR-ligand-specificity, accessory or outlaw activation of the AR by peptide growth factor/cytokine signaling pathways as well as intracrine steroidogenesis [2], [3], and [4]. Although mCRPC cells do no longer respond to traditional ADT, they are not fully refractory to further hormonal manipulations as evidenced by the clinical efficacy of second generation treatments like abiraterone, enzalutamide/MDV3100 and ARN-509 [5], [6], and [7]. Failure of endocrine treatment is often associated with the emergence of constitutively active, C-terminally truncated androgen receptor (AR) variants, lacking the entire or vast parts of the hormone/ligand binding domain (LBD) [8], [9], [10], and [11]. Devoid a LBD, these AR-variants are insensitive to all forms of endocrine therapies targeting directly (anti-androgens) or indirectly (castration) the AR-LBD and are thought to drive therapeutic failure of second generation compounds like abiraterone or enzalutamide [10] and [11].

2. Structure and function of the AR

The AR is a hormone inducible transcription factor of the steroid receptor superfamily. The human AR gene maps to band q11-12 of the X-chromosome and is organized in 8 canonical exons, all of which contribute to a full length 110 kDa AR-protein of 920 amino acids (aa) in length (Fig. 1, Fig. 1S) [2]. Like all steroid receptors the AR-protein is structurally organized in three major functional domains: an amino-terminal transactivation domain (NTD/TAD) followed by a central DNA binding domain (DBD) carrying two zinc finger motifs involved in DNA-recognition (Z1) and receptor dimerization (Z2) and a ligand binding domain (CTD/LBD) at the carboxy-terminal region. The latter carries a recently identified nuclear export signal (NES) that is inactivated upon androgen binding (Fig. 1) [12]. The LBD and the DBD are separated by a small flexible linker, the hinge region (HR) (Fig. 1). Interestingly, the HR is far more than a simple linker between LBD and DBD as it contains parts of a bipartite nuclear localization signal (NLS) [13] and [14], a microtubule binding domain (MBD) (Fig. 1) [15] as well as various target sites for ubiquitination, methylation, acetylation (lysine 630, 631, 632) and phosphorylation (serine 651) (Fig. 1S) of the AR [16].

Fig. 1

Fig. 1 Schematic overview of the different functional domains of the AR. NTD/TAD, N-terminal domain/transactivation domain; DBD, DNA binding domain; CTD/LBD, C-terminal domain/ligand binding domain; HR, hinge region; MBD, microtubule bindig domain; NES, nuclear export signal; NLS, nuclear localization signal; C, carboxy-terminal end; N, amino-terminal end; Z, zinc finger; numbers 1-920 correspond to amino-acids of the AR-protein (new nomenclature according to NCBI reference sequence NM_000044.2).

In the absence of androgens the AR resides in the cytoplasm. Upon androgen binding the AR-protein undergoes a conformational change leading to an inactivation of the NES, thereby activating the NLS-driven nuclear translocation of the AR [12] and [17]. In the nucleus the AR molecules interact to form dimers. Subsequently, the resulting AR-homodimer activates/represses the expression of AR-dependent genes [17].

3. Structure and function of C-terminally truncated AR-variants

Early functional in vitro studies showed a high constitutive transcriptional activity in AR-constructs in which the LBD has been artificially deleted [18]. Devoid a functional LBD situated in the AR C-terminus, these AR-variants are generally referred to as ARΔLBD. Over the past decade mRNAs coding for >20 naturally occurring ARΔLBD-variants have been identified in cell lines, xenografts and tissue specimens of PCa [19]. However, the expression of ARΔLBDs is not limited to prostatic tissue as recently evidenced by the detection of ARΔLBDs in cell lines and tissue of the breast, liver and kidney [20] and [21].

Most ARΔLBD-variants are products of alternative splicing (AR-V), presenting either insertions of cryptic exons immediately downstream of the exons coding for the DBD (AR-V7) or exhibiting deletions of LBD coding exons, the latter leading to a disruption of the open reading frame and expression of LBD-truncated AR-proteins (AR-V12/ARv567es = 5,6,7 exon skipped) (Fig 1 and Fig 2). In both cases the resulting splice variants present with a unique AR-V-specific C-terminal sequence/peptide (Fig. 2) [22]. In addition, nonsense mutations leading to premature chain termination (Q641X, formerly Q640X, Fig. 1S) as well as enzymatic cleavage (tr-AR) were also shown to give rise to ARΔLBDs (Fig. 2) (Table 1) [8] and [9]. Although ARΔLBDs largely differ in their synthesis, they can be subdivided into two structurally different subgroups depending on the presence or the absence of a HR (Fig. 2) (Table 1).

Fig. 2

Fig. 2 Overview and structure of AR and ARΔLBDs. (A) AR gene structure: Schematic representation of the AR-gene locus with 8 canonical exons and cryptic exons for alternative splicing. CE, cryptic exon; I, intron. (B) Structure of AR (wild type) and ARΔLBD transcripts.

Table 1 ARΔLBD variants and their characteristics in prostate cancer.

AR-V1 AR4 3/CE1 HR to LBD MTLG AAVVVSERILRVFGVSEWLP* conditional [30] and [38]
AR-V2 AR1/2/2b 3/3/CE1 HR to LBD MTLG AVVVSERILRVFGVSEWLP* constitutive [37]
AR-V5 3/CE2 HR to LBD MTLG D* constitutive [37]
AR-V6 3/CE2 HR to LBD MTLG AGSRVS* constitutive [37]
AR-V7 AR3 3/CE3 HR to LBD MTLG EKFRVGNCKHLKMTRP* constitutive [30]
AR-V8 3/intron 3 HR to LBD MTLG GFDNLCELSS* constitutive [30]
AR-V11 3/intron 3 HR to LBD MTLG GKILFFLFLLLPLSPFSLIF* unknown [30]
AR-V12 ARv567es 4/8/9 LBD (disrupted) KALP DCERAASVHF* constitutive [25]
AR-V13 6/9 LBD (disrupted) LFSI NHT* inactive [25]
AR-V14 7/9 SVQ ITPDAMYL* unknown [25]
AR-V16 8/9 KSHM ITPDAMYL* unknown [20]
Q641X Q640Stop, Q640X nonsense mutation LBD MTLGARKLKKLGNLKL* (point mutation leading to premature stop codon) constitutive [8]
tr-AR enzymatic cleavage LBD MTLGARKLKKLGNLKLQEEGEASST (enzymatic cleavage of AR-protein at aa 648/649) constitutive [9]

ARΔLBD types: AR-V1- AR-V18, splice variants; Q641X nonsense mutation; tr-AR, ARΔLBD generated by enzymatic cleavage.

Abbreviations: CE, cryptic exon; HR, hinge region; LBD, ligand binding domain; ZF, zinc finger; U, unique C-terminal peptide sequence before in frame stop codon (*); bold characters, terminal amino acids encoded by canonical exons preceding U; exon 2 (RAAE), exon 3 (MT, MTLG), exon 4 (KALP), exon 6 (LFSI), exon 7 (SVQP), exon 8 (ILSG, KSHM).

In CRPC the formation of ARΔLBDs is rapid and tightly regulated physiological process. With the exception of the nonsense mutant Q641X, the intracellular levels of ARΔLBDs like AR-V7 or tr-AR are up-regulated under androgen-deprived conditions [9] and [23]. Conversely, the induction of AR-V7 or tr-AR can be reversed through reactivation of the androgen/AR-signaling axis in PCa cells [9] and [23]. A prerequisite of all AR-molecules to exert their genomic functions is their ability to enter the nucleus. In contrast to the canonical AR-signaling pathway, the mechanisms enabling ARΔLBDs to enter the nucleus are less clear. Depending on the presence/absence of a HR some constitutively active ARΔLBDs express a NLS (Q641X, tr-AR, ARv567es) whereas others do not (AR-V3, AR-V4, AR-V7) (Table 1) (Fig. 2). While the nuclear import of HR-positive ARΔLBDs is strongly supported by the canonical NLS, the mechanisms allowing HR/NLS-negative ARΔLBDs to enter the nucleus are largely unknown. There is experimental evidence that a truncated AR-molecule consisting only of a TAD and a DBD (i.e. TAD-DBD-core) exhibits a basal level of nuclear translocation, sufficient for the induction of ligand/androgen-independent transcriptional activity [24]. In transcriptionally active ARΔLBD-splice variants, the basal TAD-DBD-core activity is thought to be regulated/enhanced by their unique C-terminal peptide (U) (Fig. 2, Table 1) [24]. In consequence different ARΔLBD splice variants show a variable capability in nuclear import depending on their structural organization (Fig 1 and Fig 2; Table 1). While AR-V7 is predominantly nuclear in the absence of androgens, AR-V1 and AR-V9 are predominantly cytoplasmic [25]. Interestingly, genomic functions of AR-Vs do not always parallel to their nuclear localization and exhibit different activities depending on the cellular context. Whereas AR-V1 and AR-V9 showed a constitutive activity in LNCaP, they were unable to do so in PC-3 cells [25]. In consequence, such AR-Vs were termed “conditionally active” to differentiate them from constitutively active variants like AR-V7 (Table 1).

Another requirement for genomic signaling of AR-molecules is their ability to form receptor dimers able to bind to the promoter region of target genes. While normal AR-molecules dimerize only in the presence of androgens, the constitutively active ARΔLBDs readily dimerize in the absence of androgenic stimuli [26,27]. In PCa cells coexpressing AR and ARΔLBDs (Q641X, AR-V7, ARv567es) there is experimental evidence for the formation of AR/ARΔLBD-heterodimers [26–28] leading to be increased nuclear AR-levels under androgen deprived conditions [26] and [27]. In consequence some authors suggest that ARΔLBDs require full-length ARs to activate the whole panel of AR-dependent genes in CRPC growing in the absence of androgens [25], [26], [29], and [30].

4. Genomic signatures of ARΔLBDs in CRPC cells

The diversity and complexity of ARΔLBD-signatures are not fully understood. Various studies tried to identify specific ARΔLBD-functions and gene expression profiles using the ARΔLBD-splice variants AR-V7 and ARv567es and the ARΔLBD-nonsense mutant Q641X as experimental models. When transfected individually into AR-negative PCa cells, all three ARΔLBDs are transcriptionally active, as demonstrated by reporter gene assays [26], [31], and [32]. However, in CRPC cells the expression of ARΔLBDs generally occurs in conjunction with the expression of a full length AR. Therefore, the effects of ARΔLBD overexpression were predominantly analyzed in the AR-positive LNCaP cells. In LNCaP grown under androgen deprived conditions, ARΔLBDs were shown to induce the expression of both androgen/AR-responsive genes [8], [33], and [34] as well as a distinct set of ARΔLBD-specific genes (Q641X: RHOB and N-Cadherin, AR-V7: N-Cadherin and UBE2C, ARv567es: UBE2C) [34], [35], and [36]. Unfortunately, the interpretation of ARΔLBD-overexpression in LNCaP cells is hampered by the fact that LNCaP express a mutated AR protein (ART878A formerly ART877A, Fig. 1S) with a broadened atypical ligand-specificity [4]. Moreover, the question whether ARΔLBDs act as ARΔLBD-homodimers or as ARΔLBD/AR-heterodimers is still a matter of debate [19], [26], [29], and [30]. The experimental findings of the current studies are limited and suggest that although constitutively active ARΔLBD-variants are able to regulate transcriptional programs involved in canonical AR-signaling, they also exhibit an individual ARΔLBD-variant specific genetic signature.

5. Role of ARΔLBDs in CRPC progression

Current evidence suggests that ARΔLBD variants may be functional drivers of PCa progression. ARΔLBDs are frequently up-regulated in CRPC as compared to hormone naïve PCa, and may emerge as an adaptive response to therapies targeting the androgen/AR-signaling axis [10], [11], [37], [38], [39], and [40]. Besides their ability to confer castration resistance, there is experimental evidence that ARv567es, AR-V7 and Q641X contribute to PCa aggressiveness through induction of epithelial to mesenchymal transition (EMT) [34], [35], [41], [42], and [43]. Most interestingly, the induction of EMT following AR3/AR-V7 overexpression in DU-145 and LNCaP cells was paralleled by an increased expression of NANOG and LIN28B, two proteins involved in stem cell renewal [43]. In line with these findings, the silencing of AR3/AR-V7 diminished the expression levels of the stem cell marker genes NANOG, OCT4 and ZEB1 in castration resistant 22Rv1 cells [43]. It is therefore tempting to speculate that ARΔLBDs contribute to PCa aggressiveness via induction of EMT and expression of stem cell marker genes.

A recent study identified a yet unknown role of AR-V7 in the regulation of cell metabolism. Using an AR-V7 inducible cell system Shafi et al. [33] was able to demonstrate that AR-V7 overexpressing PCa cells strongly enhance glutamine metabolism (glutaminolysis) via reductive carboxylation. The authors suggest that these metabolic pathways allowing the tumor cells to grow more efficiently in an oxygen poor environment, might represent a potential therapeutic target for AR-V7 over-expressing cells.

6. Detection of ARΔLBDs in prostate cancer and their role as progression markers

A number of methods have been used to detect AR-Vs in CRPC specimens (Table 2). Taking advantage of their unique exon compositions and exon-exon junctions (Table 1) different AR-V transcripts can be reliably detected by reverse transcription polymerase chain reaction (RT-PCR) [39]. In consequence quantitative RT-PCR (qRT-PCR) is the preferred method for the analysis of AR-V expression levels in cell cultures and tissue specimens [25] and [39]. However, other promising methods allowing to analyze AR-V transcripts like RNA in situ hybridization (RISH) or RNA sequencing (RNAseq) are currently being tested [44] and [45]. Based on the assumption that ARΔLBDs are functional drivers of tumor progression and therapy failure [38], [39], [40], and [46], Antonarakis et al. [47] developed a non-invasive test for the analysis of AR-V7 expression in circulating tumor cells (CTC) from patients suffering from advanced PCa. Interestingly, expression of AR-V7-mRNA in CTCs predicted a lack of PSA response to enzalutamide and abiraterone and was correlated with progression and shorter survival. Moreover, the authors showed that treatment with abiraterone and/or enzalutamide resulted in an increased expression of AR-V7. A similar study demonstrating the association between CTC-AR-V7 expression and resistance to both enzalutamide and abiraterone recently confirmed the potential role of AR-V7 as a progression marker [48].

Table 2 Methods for the detection of AR-Vs in CPRC.

RT-PCR cell cultures tissue specimens, biopsies, fresh frozen tissue, CTCs highly sensitive lower sensitivity in FFPE tissue [28] and [39]
RISH cell cultures, FFPE tissue,
fresh frozen tissue
intracellular localization of mRNA detection of pre-mRNA [44]
RNAseq cell cultures, FFPE tissue,
fresh frozen tissue
high quantitative accuracy costs [45]
IHC/IF cell cultures, FFPE tissue,
fresh frozen tissue
intracellular localization
of functional proteins
limited number of AR-V specific antibodies [38] and [46]
Western Blot cell cultures, FFPE tissue,
tissue specimens, biopsies
detection of all ARΔLBD proteins (AR-V, Q641X, tr-AR) limited number of AR-V specific antibodies, optimization and standardization of N-C subtraction method [25], [28], and [38]

Abbreviations: CTCs, circulating tumor cells; FFPE, formalin-fixed, paraffin-embedded; IF, immunofluorescence; IHC, immunohistochemistry; RISH, RNA in situ hybridization; RNAseq, RNA sequencing; RT-PCR, reverse transcription polymerase chain reaction.

Although qRT-PCR provides a highly sensitive and specific assay for the detection of AR-V transcripts (especially in CTC), the presence of AR-V mRNA does not always correlate with AR-V protein expression [22] and [39]. Unfortunately, the precise analysis of this phenomenon is hampered by the fact that isoform specific antibodies for Western Blot and immunohistochemistry/immunofluorescence (IHC/IF) have only been reported for AR-V7 and AR-V12/ARv567es. To overcome this limitation Zhang et al. [40] developed an immune-histochemical approach by using two different antibodies recognizing the AR-N-terminus (TAD) and AR-C-terminus (LBD), respectively (Fig. 1). To estimate the abundance of LBD-truncated ARΔLBDs the authors compared N- and C-terminal immunoreactivity in the nucleus (N-C subtraction method). A decrease of AR-nuclear staining by the C-terminal antibody in comparison to the staining pattern with the N-terminal antibody indicated the presence of LBD-truncated, constitutively active ARΔLBDs [40]. First clinical studies using AR-V7 directed antibodies in IHC-studies showed that the AR-V7 protein is commonly up-regulated in CRPC and rises as an adaptive response to therapies targeting the canonical androgen/AR signaling axis [38], [39], and [46]. Although there are some discrepancies between AR-V7 mRNA and protein data [22] and [39], AR-V7 mRNA and/or protein present highly interesting new prognostic as well as therapeutic targets.

7. Novel therapies targeting ARΔLBD-signaling

The AR has been the target for most systemic therapies for more than 70 years and counting. With the emergence of constitutively active ARΔLBDs in late stage CRPC all current endocrine therapies targeting the LBD are prone to fail. In consequence there is an urgent need for novel compounds able to inhibit the AR in a non-LBD dependent manner. Only a few compounds namely taxanes and galeterone are currently tested in the clinic for late stage AR-V7 positive CRPC.

There is experimental evidence from in vitro studies that first-generation taxanes like docetaxel and paclitaxel are able to impair the nuclear localization of the AR via modulation of the microtubule machinery [4], [15], and [49]. Two independent studies suggest that only the activities of AR/ARΔLBDs carrying a microtubule-binding domain (MBD) in their HR (AR, ARv567es), are affected by docetaxel-mediated microtubule stabilization [15] and [50]. Conversely, the HR/MTB-negative AR-V7 (Fig 1 and Fig 2) is unable to associate with the microtubules and accumulates in the nucleus where it activates the transcriptional machinery [15]. However, the ability of taxanes to modulate AR-signaling in the clinical setting yielded controversial results [51] and [52]. The discrepancy between in vitro and in vivo results could be explained by the fact that the taxane concentrations used to modulate AR/ARv567es-signaling in vitro, are far beyond the concentrations achievable in vivo[51].

One of the most promising compounds currently being tested in the clinic for the treatment of CRPC is galeterone (ARMOR3-SV, currently recruiting). Galeterone, (previously known as VN/124-1 or TOK-001) acts through its dual activities as a CYP17A1-inhibitor and anti-androgen [53]. In addition Yu et al. [54] reported that the compound prevents AR binding to chromatin and enhances degradation of the AR-mutant ART878A. Most importantly, galeterone was recently shown to induce a proteasomal degradation of the splice variants AR-V7 and ARv567es trough an MDM-2 dependent mechanism [55].

Niclosamide, an FDA-approved anti-helminthic drug, was shown to downregulate the expression of AR-V7 protein via proteasomal degradation. In line with this observation, niclosamide was shown to reverse enzalutamide resistance in CRPC cells [56]. The authors suggest that an enzalutamide/niclosamide combination therapy might be a treatment option for otherwise highly resistant CRPC [56].

Current AR directed therapies concentrate on targeting the structurally well studied C-terminal LBD. Unfortunately the development of N-terminal AR-inhibitors is hampered by the intrinsic disorder of the AR-N-terminus, making drug development labor intensive and requiring numerous assays that test each drug empirically [57]. Despite these difficulties, three separate classes of inhibitors of the AR-NTD have recently been described: a. decoy peptides to the AR NTD, b. sintokamides (peptides isolated from Dysidea sp. a marine sponge) and c. the bisphenol derivativeEPI-001 [58], [59], and [60]. In a first series of experiments EPI-001 exhibited a significant antitumor activity that was paralleled by a strong inhibition of AR and ARΔLBD activity in vitro and in vivo[60]. A Phase I study by ESSA Pharmaceuticals, testing EPI-506 an EPI-001 derivate is currently recruiting in the US and Canada (see https://clinicaltrials.gov).

A further approach to inhibit the AR-N-terminus and its TAD is the inhibition of BET bromodomain proteins. There is experimental evidence that BET bromodomain proteins associate with the AR-N-terminus, thereby controlling AR-mediated transcriptional programs [61]. Treatment of CRPC cell lines with the BET-inhibitor JQ1 diminished AR/ARΔLBD-signaling thereby inducing apoptosis and cell cycle arrest in these cells [61] and [62].

Stilbenes like resveratrol have repeatedly been shown to modulate AR-signaling [28], [63], [64], and [65]. Using reporter gene assays Streicher et al. [28] demonstrated that two stilbenes, namely resveratrol and (E)-4-(2, 6-Difluorostyryl)-N,N-dimethylaniline were able to inhibit the dimerization of AR and Q641X, thereby dramatically reducing their transcriptional activities. The authors suggest that stilbenes might serve as lead compounds for a novel generation of inhibitors targeting AR/ARLBD-dimerization processes [28].

In addition to the regulation by steroids, the AR is also regulated by posttranslational modifications like serine/threonine or tyrosine phosphorylation, generated by peptide growth factor and/or cytokine signaling pathways [66]. As most AR phosphorylation sites are located at the N-terminus, a region shared by both, full length AR and ARΔLBD, it was hypothesized that kinase inhibitors might be able to affect AR/ARΔLBD-function. Indeed, treatment of PCa cells with the multi-kinase inhibitor sorafenib was shown to inhibit the activity of the AR and Q641X in reportergene assays [67]. Moreover, long term treatment with sorafenib, lead to a proteasomal degradation of both AR and AR-V7 of 22Rv1 cells [67]. Since the insulin like growth factor 1 (IGF-1) pathway was repeatedly shown to affect AR function, we studied whether an inhibition of the IGF-1 receptor (IGF-1R) could also affect ARΔLBD activity. Inhibition of IGF-1R led to a down-regulation of AR, Q641X and AR-V7-signaling in PCa cells [68]. Moreover inhibition of ARΔLBD-signaling was paralleled by a decrease in N-terminal phosphorylation as evidenced by a decrease of serine 83 (formerly Ser 81, refer to Fig. 2S) phosphorylation in the ARΔLBD Q640X/Q641X [68]. In summary, the current data suggest that the IGF-1/IGF-1R axis is a modulator of the ARΔLBD signaling providing a rationale for developing growth factor receptor-targeting therapies for mCRPC.

8. Conclusions

Despite high initial response rates, the benefits from ADT are only transitory. With the emergence of constitutively active, c-terminally truncated ARΔLBDs like AR-V7 or ARv567es current endocrine treatments including next generation compounds like enzalutamide and/or abiraterone are prone to fail. Increasing evidence highlight the concept that especially AR-V7 could be used as a potential predictive biomarker and a therapeutic target in advanced prostate cancer.

Appendix A. Supplementary data

The following are Supplementary data to this article:


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a Department of Urology, Ulm University Medical School, 89075 Ulm, Germany

b Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany

c Department of Pediatric Surgery and Pediatric Urology, University Hospital Tübingen, 72076 Tübingen, Germany

Corresponding author at: Department of Urology University Hospital Schleswig Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.