Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations



The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance.


We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics.


Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR-V7 remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 coexists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their coregulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain.


Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.


Prostate cancer is an androgen-dependent disease. Management of patients with advanced prostate cancer often involves androgen-deprivation therapies (ADT) established in 1941 [1]. Under ADT, castrate levels of androgens indicated by circulating testosterone (T) less than 50 ng/dL are achieved. Castration-resistant prostate cancer (CRPC) defines disease progression under castrate levels of T. In CRPC, expression level of the androgen receptor (AR) is often elevated, leading to AR activity under reduced androgen levels. In addition, the AR gene on the X chromosome may undergo genomic alterations including structural changes and point mutations. These CRPC-specific AR alterations provided a mechanistic explanation for continued dependence of CRPC on AR signaling [2,3,4]. This important concept in CRPC biology has guided and resulted in successful clinical development of second-generation AR-targeting therapies to treat CRPC, including agents that antagonize AR (enzalutamide, apalutamide, darolutamide) or further suppress extragonadal androgen synthesis (abiraterone, orteronel) [5,6,7,8,9,10,11,12,13,14,15,16,17]. The next-generation AR antagonists bind to the AR ligand-binding domain (LBD) with higher affinity than first-generation antiandrogens [6, 8], while abiraterone inhibits CYP17A1, a rate-limiting enzyme in the synthesis of adrenal and intratumoral androgens [5, 7]. Recently, clinical use of these next-generation AR-targeting therapies has been extended to castration-sensitive prostate cancer (CSPC) [9, 18, 19] and nonmetastatic CRPC [10,11,12, 20,21,22].

AR variants (AR-Vs) have mRNA sequences that are structurally different from the canonical full-length AR (AR-FL). A total of 22 AR-Vs have been cloned and reported in the literature (Fig. 1). The majority of these AR-Vs lack the LBD, the therapeutic target of all existing AR-targeting agents. In preclinical models, some but not all of these AR-Vs mediate constitutively active AR signaling, i.e., their activity is not dependent of the presence of androgens or AR-FL [23]. Among the AR-Vs described to date, AR-V7 remains to be the most extensively evaluated and characterized, and several blood-based tests for AR-V7 have been developed (see companion review). General topics on AR-Vs have been reviewed extensively in the past [23,24,25,26]. The intent of the current review is to provide a sequel to a previous review article published in 2016 [24]. Specifically, we will highlight recent preclinical studies covering topics ranging from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We will provide expert opinions and perspectives on these topics. Readers are directed to a companion review focusing on clinical studies related to AR-Vs.

Fig. 1: Decoding the androgen receptor splice variant transcripts.

a AR gene structure with canonical and cryptic exon splice junctions marked according to GRCh37/hg19 human genome sequences (not drawn to scale); b Nomenclature, functional annotation, exon compositions, and variant-specific mRNA (color matched to a) and peptide sequences (in gray). Modified from [70].

Advances in AR-V measurement and detection methods

Accurate, reliable, and reproducible measurement of AR-Vs is a key requirement for inferring functional and clinical relevance. A variety of detection methods have been developed for the measurement of AR-Vs. These methods differ according to the method of sampling and specific measurement target. Some methods developed for blood-based AR-V7 detection have been analytically validated and implemented for clinical use (see companion review).

Detection by CTC mRNA

Blood-based detection of AR-V7 in the treatment setting was first reported in 2014 [27]. In this initial report, CTC enrichment was achieved by AdnaTest, followed by RT-PCR-based detection of AR-FL and AR-V7. Following analytical validation, a slightly modified version of the laboratory-developed test was implemented in a CLIA- and CAP-certified laboratory for clinical use [28, 29], and another modified version was implemented as a clinical trial test [30]. The AdnaTest employs a simple workflow enabling fast turnaround time at low cost, but with the drawback of requiring sample processing within 24 h of blood collection. Nevertheless, with careful management this drawback can be overcome. For example, a global biomarker selection trial was conducted by Tokai after implementing three central laboratories in three continents [30]. A recent prospective study further validated the feasibility of conducting the test in the multi-institutional setting involving overnight shipping [13]. While analytical and clinical validity are the two key requirements for clinical implementation, further improvement of the CTC-based test should take into consideration many factors that may also impede or facilitate clinical implementation, including cost and ease of use. Because the number of CTCs detected is always the limiting factor, new technologies to improve efficiency/sensitivity of CTC enrichment may further improve the test. For example, novel microfluidic apparatus or in vivo CTC collection methods were designed for CTC isolation and molecular analysis. Using negative depletion microfluidics (CTC-iChip) [31] ( NCT01961843) or positive selection microfluidic chip (e.g., IsoFlux) [32], CTC mRNA analysis including analysis of AR-FL/AR-V7 were conducted with digital droplet PCR (ddPCR). An intravascular CTC collection rod with antibody-coated surface (CellCollector, Gilupi, Germany) [33,34,35], as well as antibody-coated magnetic wire designed for CTC collection directly from blood flow [36], may also help to address the limitation of low CTC numbers. With regard to the limitation posed by low amount of CTC RNA, multiplexing may be the solution. For example, a 27-gene panel (iGene panel) was tested with high-throughput qPCR on Biomark platform (Fluidigm, San Francisco, CA) from CRPC patients receiving docetaxel treatment [37]. These technologies may be used for biomarker development, including the detection of AR-Vs. However, it is challenging to conduct direct comparison of various CTC-based mRNA detection platforms.

Detection in whole blood

AR-Vs may be detected in whole blood without CTC enrichment. Using blood collection tube containing additives for the purpose of stabilizing intracellular RNA (e.g., PAXgene Blood RNA tube), total RNA from peripheral blood were prepared for AR-V7 detection [38,39,40,41]. However, mainly due to RNA contamination from large amount of leukocytes, the tumor-cell origin of AR-V7 will need to be validated especially when the measured signals are low. In addition, it is important to note that measurement of AR-FL is no longer possible in whole blood samples because non-CTC cells such as regulatory T cells and macrophages have low level of AR expression [42, 43].

Detection in exosomes

Exosomal RNA from extracellular vesicles in plasma represents another source for AR-V detection. Using exosomes, AR-V7 was detected by ddPCR using TaqMan probe with high sensitivity (at 2 copies/mL blood) and shown to be a strong predictive marker for enzalutamide/abiraterone resistance in mCRPC patients [44]. In another report, extracellular vehicles from urine were used in detecting AR-V7 [45]. Again, studies designed to conduct head-to-head comparisons are important but challenging to implement in the treatment setting.

Tissue detection by RNA in situ hybridization (RISH)

PCR-based detection methods described above are in-solution methods that generally do not capture cellular heterogeneity and the morphological context in tumors. In situ detection methods such as RISH and immunohistochemistry (IHC) (see below) have been developed. The use of RISH for AR-V7 detection was first reported in 2014 [27]. Subsequently, different types of probes, including padlock probes, modified branched DNA probe, or junction-specific probes with enhanced sensitivity and specificity were developed to evaluate AR-FL and AR-Vs in FFPE tissue biopsy and isolated CTCs [34, 46,47,48]. In these studies, higher AR-V7 levels were associated with poorer response to AR-targeting therapies in mCRPC [47, 48].

Tissue detection by IHC

Recent studies on in situ detection of AR-V7 protein by IHC focused on newly developed and validated antibodies [48,49,50,51,52,53]. Using matched CSPC and CRPC tissue samples, nuclear AR-V7 protein detected by a rabbit AR-V7 monoclonal antibody (EPR15656; Abcam, Burlingame, CA) was associated with poor prognosis of CRPC patients after abiraterone or enzalutamide treatment [51]. Following detailed characterization in clinical cohorts [13, 49, 54], the EPIC CTC AR-V7 IHC test (Epic Sciences, San Diego, CA) initially developed using the same anti-AR-V7 antibody was recently implemented for clinical use (see companion review). In tissue-based studies, the use of the RM7 (RevMab) antibody further established CRPC-specific expression AR-V7 [48, 50, 55]. Interestingly, AR-V7 protein expression was detected using this well-validated antibody in a subset of cells in small cell prostate carcinoma and some salivary ductal carcinoma specimens from untreated female patients [52, 56]. These recent studies on AR-V7 protein expression further supported that AR-V7 expression arises specifically in a low-androgen environment.

Tissue detection by NGS

AR-Vs can be detected in clinical specimens by RNA-seq [27]. In Antonarakis et al., two autopsy specimens from mCRPC patients with positive CTC AR-V7 underwent RNA-seq analysis. Using number of reads spanning the exon 3/cryptic exon 3 (CE3) and exon 7/exon 8 junctions as surrogate expression values for AR-V7 and AR-FL, respectively, the AR-V7/AR-FL ratios in the two samples were 25.8% (139/539) and 12.1% (151/1248), in line with AR-V7/AR-FL ratios (median 21%, range 1.8–208%) estimated from RT-PCR-based CTC AR-V7 test reported in the same study. Using a slightly different method, the median AR-V7/AR-FL ratio from a larger-scale study of CRPC tissues was estimated at ~5% [57]. The lower % reported in tissue-based studies is expected and does not contradict with our initial report in unselected CRPC tissues [58] or the ratios reported in CTC AR-V7 positive cases, because higher ratios reported in the Antonarakis study [27] excluded CTC AR-V7 negative cases (no ratios can be calculated in AR-V7 negative cases). In addition, RNA-seq in primary hormone-naive prostate cancers also detected AR-V7 at slightly lower AR-V7/AR-FL ratio [59]. This is not unexpected either, as primary PC tissues are known to have low levels of AR-V7 detected by RT-PCR [58]. However, we previously posited [24] that since AR-FL is also overexpressed in CRPC, a ratio of AR-V7/AR-FL at 10%, under the assumption of tenfold overexpression of AR-FL in CRPC tissues, would bring the absolute level of AR-V7 equivalent to the level of AR-FL detected in primary hormone-naive prostate cancers tissues. This interpretation also explained why AR-V7 protein is not detected in primary tissues [50].

Recent AR-V studies using whole-genome sequencing

Recent studies have used whole-genome NGS to examine AR for DNA structural alterations and RNA expression. Henzler et al. [60] evaluated 30 soft tissue metastases from 15 rapid autopsies for AR structural changes and AR-V expression. In this study, diverse AR-genomic structural rearrangements (AR-GSRs) including deletion, duplication, inversion, and translocation were observed in 10/30 metastases (6/15 patients). This study discovered many novel AR-Vs driven by AR-GSR. Cloned AR-Vs are depicted in Fig. 1. A pilot study by De Laere et al. [61] applied NGS to CTC and cell-free DNA (cfDNA) from mCRPC patients. In this study, cfDNA was evaluated by low-pass whole-genome sequencing and targeted sequencing of 112 genes including all coding exons and nonrepetitive intronic regions of AR, and expression levels of AR-FL and AR-Vs (AR45, AR-V1, AR-V2, AR-V3, AR-V5, AR-V7, and AR-V9) were interrogated by amplicon sequencing from multiplex junction-specific PCR using cDNA derived from CTCs. In 30 CTC samples from 26 mCRPC patients, 15/26 (57.7%) patients were AR-V-positive with AR-V7 being the most frequently detected variant (12/15 patients), followed by AR-V3 (11/15), AR45 (10/15), AR-V9 (6/15), AR-V1 (5/15), AR-V2 (3/15), and AR-V5 (3/15). In this study, 50% (15/30) of cfDNA samples had an intra-AR structural variation, and 14 of these 15 samples were positive for AR-Vs. Within the small cohort of patients treated with abiraterone or enzalutamide, 15/26 (57.7%) were AR-V-positive, and positive patients were either resistant (13/15) or moderately responsive (2/15) to abiraterone or enzalutamide.

Kallio et al. also applied targeted AR DNA-seq and RNA-seq to examine AR-Vs and other AR aberrations in CSPC, CRPC, mCRPC, BPH, and noncancerous tissues [62]. AR-V3, AR-V7, and AR-V9 were most frequently detected and coexpressed AR mRNA variants in mCRPC, and these variants were also detected in BPH and hormone-naive primary tumors with lower abundance and frequency, although corresponding protein expression (in BPH and hormone-naive samples) was not shown. AR mutations and copy number changes were only detected in locally recurrent and metastatic CRPC specimens but not in untreated patients. Nonrecurring AR-GSRs (i.e., breakpoints are unique to each sample) were also specifically detected in 5/30 mCRPC. In this study, no AR-GSR coexisted with AR missense mutations in mCRPC [62]. In addition, no definitive association was found between these AR-GSRs and AR-Vs, in line with the finding by Henzler et al. [60].

Due to limitation of short-read NGS sequencing by Illumina, the contribution of AR-GSR to AR-V generation remains to be thoroughly investigated. To date, only one study used a long-read sequencing method (PacBio sequencing platform) to characterize AR-Vs. In this prospective biomarker study (PROMOTE trial, NCT01953640), Kohli et al. performed targeted AR RNA-seq, whole transcriptome sequence, and long-read sequencing of AR 3′ rapid amplification of cDNA ends products in cell lines, patient-derived xenograft, and metastatic CRPC biopsy tissue samples [63]. Expression of AR and AR-Vs was also measured by qRT-PCR in CTC samples. This study found that the 3′ UTR of AR-V9 included CE3 of AR-V7, and high-level of baseline AR-V9 was associated with resistance to abiraterone [63].

Molecular origin and regulation of AR-V expression

It is well established that expression of AR-Vs are regulated by androgens [64,65,66,67,68,69]. Since our last review in 2016 [24], many studies have been published that are relevant to the topic of molecular origin and regulation of AR-V expression. We will summarize the current literature on this topic in the following three general categories: (1) studies focusing on the role of genomic alterations; (2) studies focusing on the role of RNA splicing; and (3) studies demonstrating the role of other cofactors and signaling pathways on regulating AR-V expression. The findings from studies focusing on splicing factors and related regulators are summarized in Fig. 2. Readers are directed to a recent review [70] for further reading on the specific topic of AR-V regulation, the role of genomic structural alterations, and the requirement of low androgens for AR-V7 generation.

Fig. 2: Regulatory mechanisms involved in AR-V expression.

Splicing factors involved in AR-V generation include U2AF65, ASF/SF2, HNRNPA1 (NFκB2/p52- and c-Myc-signaling related), and SAP155. LncRNAs involved in splice factor binding to AR pre-mRNA include PCGEM1 (p54/nrb signaling related) and MALAT1. Epigenetic modifier KDM3A may bind AR pre-mRNA and recruit HNRNPF and U2AF265. RNA helicase DDX39A and DDX39B and RNA-binding protein LIN28. Inhibition of CPSF1 by siRNA with morpholinos targeting a single polyadenylation signal (PAS) in AR CE3 suppresses AR-V7/V9 expression. Several protein kinase pathways, e.g., AKT/ERK/YB-1, and noncoding RNAs including circRNA17 and miR-181c-5p may also be involved in AR-V expression. Refer to text descriptions for details.

Role of genomic alterations

AR-GSRs underlie the generation of some of the AR-Vs. As discussed in “Recent AR-V studies using whole-genome sequencing”, AR-GSRs may also contribute to the generation of AR-Vs [60,61,62,63]. In an interesting model proposed by Henzler et al., successive structural alterations may occur on the same AR allele, leading to generation of AR-Vs. The study presented a case in which tumors from multiple metastatic sites in the same patient showed similar complex patterns of deletion and duplication within the AR LBD that explained the dominant expression of ARv567es [60]. However, due to the limitation of short-read sequencing and the involvement of target enrichment, this model may need further validation with long-read genomic sequencing.

Role of RNA splicing

Although CRPC-specific splicing factors involved in the process have not been definitively identified, studies focusing on factors that regulate AR splicing have identified several key factors related to the RNA spliceosome. On the basis of predicted intronic/exonic splicing enhancer sequences in CE3 of the AR gene, ChIP and RNA-pull down assays were performed and identified U2AF65 (splicing factor U2AF65 kDa subunit, aka U2AF2, U2 small nuclear RNA auxiliary factor 2) and ASF/SF2 (alternative splicing factor 1/splicing factor 2) as two key factors mediating AR-V7 splicing [65]. A general splicing factor HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1) was also reported to regulate AR-V7 expression in prostate cancer cells. Activation of NFκB2/p52 and c-Myc signaling resulted in recruitment of HNRNPA1 to the splice site of AR pre-mRNA to promote AR-V7 expression [71].

The ADT-induced lncRNA prostate cancer gene expression marker 1 (PCGEM1) was also implicated in AR-V7 generation. PCGEM1 regulates the binding of splice factors HNRNPA1 and U2AF65 to AR pre-mRNA [72]. In addition, p54/nrb (nuclear RNA-binding protein, aka NONO, non-POU domain-containing octamer-binding protein), a nuclear protein with multiple functions in RNA splicing and gene regulation, positively regulates PCGEM1 expression, as revealed by DNA-pull down assay using PCGEM1 gene promoter in prostate cancer cells [73]. Suppression of p54/nrb by siRNA or a natural compound from cruciferous vegetables that interferes with p54/nrb-DNA binding resulted in reduced expression of PCGEM1 and AR-V7 [73].

Natural spliceosome inhibitors, thailanstatins (TST-A or TST-D), were used to investigate the relationship between AR-V7 and splice factors SAP155 (spliceosome-associated protein 155, aka SF3B1, splicing factor 3b subunit 1) and U2AF65. TSTs interrupt the interaction between U2AF65 and SAP155 leading to reduced binding to the polypyrimidine tract located between the branch point and the 3′ splice site, and consequentially reduced AR-V7 expression [74].

AR-V7 may be regulated by Jumonji domain containing 1A (JMJD1A, aka KDM3A), a histone demethylase that removes the repressive H3K9 methylation marks (H3K9me1 or H3K9me2) [75]. KDM3A also interacts with AR as an AR coactivator to regulate prostate cancer cell proliferation and survival by altering AR transcriptional program and elevating c-Myc levels [76,77,78]. KDM3A promotes alternative splicing of AR-V7 by binding to guanosine (G)-tract sequences in CE3 of the AR gene leading to recruitment of heterogeneous nuclear ribonucleoprotein F (HNRNPF) and other splice factors such as U2AF265 [75].

DDX39 [DEAD (Asp-Glu-Ala-Asp) box polypeptide 39] is an ATP-dependent RNA helicase implicated in RNA splicing, mRNA export, and telomere structure integrity. Using a shRNA library focused on 88 spliceosome-related genes, DDX39B was found to be a regulator of AR-V7 expression [79]. After knockdown of DDX39B and its paralogue DDX39A in AR-V-expressed cells, the AR-V7 mRNA was selectively downregulated [79].

LIN28 is an RNA-binding protein involved in AR and c-Myc signaling in prostate cancer. Overexpression of LIN28 in PCa cell lines resulted in increased AR splice variant expression and resistance to antiandrogens. Downregulation of LIN28 can resensitize PCa cells to enzalutamide treatment [80].

The long noncoding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was also implicated in regulating AR-V7 activity. Using enzalutamide-resistant prostate cancer cell lines, AR-V7 and MALAT1 were both elevated when AR signaling is suppressed. AR negatively regulates MALAT1 by direct binding to androgen response elements (AREs) in the promoter of MALAT1. Increased MALAT1 during AR suppression by enzalutamide could elevate AR-V7 transcription through interaction between MALAT1 and serine/arginine rich splicing factor 1 (SRSF1, aka ASF/SF2). CRPC progression in animal models was suppressed following MALAT1 knockdown [81].

Other cofactors regulating AR-V expression

Protein kinase pathways may regulate AR-V expression. The most relevant is the AKT pathway, which modulates AR function and mediates survival signaling in CRPC. In a screen of kinase inhibitors involving a 145 small‐molecule compound library and a high-throughput siRNA-kinome library, several kinases including Akt, Abl, and Src family kinases were found to regulate AR-V7 mRNA expression and protein nuclear translocation. Following treatment of CWR22Rv1 cells with a Src/Abl dual kinase inhibitor PD180970, AR-V7 protein was decreased and cell proliferation inhibited in the absence of DHT. In the presence of DHT (when AR-FL is activated), the potency of PD180970 was decreased. Pretreatment with AR-FL antagonist bicalutamide resensitized CWR22Rv1 cells to PD180970 with a substantial EC50 drop (from 184.2 to 12.6 nM) in the presence of DHT [82], suggesting that PD180970 reduced AR-V7 protein level and CWR22Rv1 growth in AR-independent manner. Tyrosine kinases such as ACK1/TNK2 regulate AR gene transcription through epigenetic modification. ACK1/TNK2 phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site, and treatment with an ACK1 inhibitor (R)-9bMS reduced AR and AR-V7 levels and suppressed CRPC tumor growth [83].

Y-box-binding protein 1 (YB-1) is a transcription factor that binds Y-box (5′-ATTGG-3′), and also a RNA-binding protein involved in RNA splicing. In a study involving kinome arrays, Akt, RSK (ribosomal S6 kinase), ERK (extracellular signal-regulated kinases, p42/44 MAPK) were found to phosphorylate YB-1 and affect AR-V7 expression [84]. Treatment of CWR22Rv1 cells with kinase inhibitors against Akt, MEK (MAPK/ERK kinase, an upstream activator of MAPK/ERK) resulted in reduced levels of phosphorylated-YB-1, AR-FL, and AR-V7. However, an inhibitor of RSK specifically downregulated AR-V7 but not AR-FL. How RSK/YB-1 signaling affects AR splicing remains largely uncharacterized [84].

The relationship of AKT signaling and prostate cancer was evaluated by a synthetic AKT inhibitor alkyl-lysophospholipid edelfosine (ET-18-O-CH3). Edelfosine interacts with lipid rafts on plasma membrane, and induce endoplasmic reticulum stress following inhibition of phosphatidylcholine biosynthesis. Treatment of LNCaP and VCaP cells with edelfosine resulted in suppression of AR-V7 expression and cell apoptosis that was enhanced by activating transcription factor 3, a corepressor of AR [85].

Other nuclear receptors may regulate AR-FL/AR-V7 expression. For example, RAR-related orphan receptor gamma (ROR-γ) recruits nuclear receptor coactivator 1 and 3 [NCOA1 and NCOA3, also known as steroid receptor coactivator (SRC)-1 and SRC-3] to an AR-ROR response element to stimulate AR gene transcription [86]. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in PCa cell lines and tumors [86]. Given that many ROR-γ inhibitors are approved for treating autoimmune disease, it may be possible to repurpose these drugs to suppress AR-V7-driven prostate cancer.

Noncoding circular RNA (circRNA) or miRNA could also regulate AR-V7 expression. By in silico analysis, a circRNA 17 (circRNA17, hsa_circ_0001427) was found to interact with microRNA 181c-5p (miR-181c-5p) leading to suppression of AR-V7 expression. By interacting with and stabilizing miR-181c-5p, circRNA17 increased the relative level of miR-181c-5p, which bound to the 3′UTR of AR-V7 transcript to downregulate AR-V7 expression. Castration can suppress circRNA17 expression by inhibiting its host gene PDLIM5 (PDZ and LIM domain 5) expression via ARE in the gene promoter. In this study, the level of circRNA17 was downregulated in clinical prostate cancer specimens especially in higher Gleason score prostate cancer specimens [87].

Genomic functions mediated by AR-Vs

As transcription factors, AR-Vs may mediate their downstream genomic functions by DNA binding and interaction with coregulators following nuclear localization. While AR-FL and many AR-Vs may share common chromatin binding sites, genomic binding sites, and transcriptional programs specific to AR-V7 have been reported [64, 88,89,90,91]. In studies relevant to this topic, it is critical to take into consideration a few premises: (1) AR-V7 protein expression is specific to CRPC and negatively regulated by androgen signaling mediated by AR-FL [64, 68]; (2) AR-V7 expression is often associated with a progressive phenotype under low-androgen conditions [64, 90]; and (3) AR-V7 often coexists with AR-FL, and whether AR-V7/AR-FL forms heterodimer under low androgen conditions will affect interpretation of data [68, 89, 92,93,94].

Since our last review in 2016 [24], a few important factors mediating downstream functional effects of AR-V7 have been characterized. Chen et al. revealed diverse AR-V7 cistromes and transcriptomes in different CRPC cell lines and clinical specimens [89]. Employing a high-resolution ChIP-exonuclease sequencing approach using an AR-V7-specific antibody, HOXB13 was found to colocalize with AR-V7 and function as an essential coactivator mediating AR-V7 function. By inhibiting HOXB13 in AR-V7-expressing cells, the oncogenic function of AR-V7 was suppressed [89]. These results implicated that HOXB13, which is very specifically expressed in tissues of prostatic origin, could be an alternative target in suppressing the development of AR-V7-driven CRPC. Cai et al. used specific antibodies against either AR-FL or AR-V7 for ChIP-seq. In this study, 15,162 out of a total of 17,409 binding sites were shared by both ARs, and only a small proportion of binding sites (about 12.8%, 2221 out of 17,409 spots) was specifically bound by AR-V7. In these AR-V7-specific binding sites, zinc finger protein X-linked was found to exclusively colocalize with AR-V7. The AR-V7-specific binding sites are mainly located at the gene promoter and these AR-V7 targeted genes were mainly involved in MYC-bound genes or genes related to cell cycles and autophagy [88].

Preclinical and early clinical development of agents targeting AR/AR-Vs

Given the availability of blood-based detection methods and the general poor prognosis of patients having positive CTC AR-V7 testing results, recent efforts have focused on development of agents that may overcome drug resistance and poor prognosis by targeting AR-V7. Several compounds with in vitro anti-AR-V7 activity have already been evaluated in clinical trials, while many others are in various stages of preclinical evaluation and development (see companion review). A comprehensive review of the current literature on possible preclinical agents and strategies returned many studies. Due to space limitations, we summarized these studies in Fig. 3 and Table 1 (with references).

Fig. 3: Novel preclinical agents that suppress AR/AR-Vs by regulating gene expression, degradation, AR transcriptional activity, and downstream signaling.

The following broad categories are summarized. Refer to Table 1 for details. (1) Targeting AR/AR-Vs translation: 6BIO + PS − LNA − AR − ASO. (2) Novel AR antagonists: EPIs, 3E10-AR411, VPC-3022, SARDs, Ad-E1A12 variant. (3) Enhancing AR or AR-Vs degradation: niclosamide, ASC-J9, alisertib, PROTAC degrader, leelamine. (4) Targeting AR chaperones: C86, VER155008, onalespib. (5) Targeting molecules involved in epigenetic modification: BETi, HDACi, CUDC-101, EZH2i, astemizole. (6) Targeting AR/AR-Vs coregulators or transcriptional activity: KCI807, triptolide/minnelide, clorgyline/phenelzine, IPI-9119, BETi. (7) Targeting AR/AR-Vs downstream signaling molecules: LY2090314, N9 + doxorubicin, G1T28/G1T38, alisertib, FrA.

Table 1 Novel agents targeting AR/AR-V signaling.


Laboratory investigations and findings reported since 2016 continue to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. These new findings further validate the importance of AR-Vs, AR-V7 in particular, in CRPC. Development of mature measurement methods have enabled detection of the AR-V targets in both liquid and tissue specimens, and quantitative measurement data on AR-V7 support its functional and clinical relevance. While AR-Vs (e.g., ARv567es) driven by complex AR-GSRs, as well as dominant expression of AR-V7 in isolated cases provide compelling examples of clonal expansion consistent with a driver role for AR-Vs in castration resistance, in most cases AR-FL continue to coexist with AR-Vs, justifying further investigations to dissect the distinct roles of the different AR molecules. In this regard, distinct genomic functions mediated by AR-FL and AR-Vs have been defined in greater details now, further supporting the therapeutic relevance of AR-Vs. Given the feasibility of conducting blood-based detection for AR-V7, the hope is that clinical development of agents possessing anti-AR-V activity can be accelerated, even in the presence of many competing mechanism that may coexist. Going forward, both challenges and opportunities exist in targeting AR-Vs to overcome resistance to current AR-directed therapies. Development of agents with specific anti-AR-V7 activity remains a top priority in prostate cancer research.


  1. 1.

    Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. J Urol. 2002;168:9–12.

    PubMed  Google Scholar 

  2. 2.

    Chen Y, Sawyers CL, Scher HI. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharm. 2008;8:440–8.

    CAS  Google Scholar 

  3. 3.

    Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell. 2009;16:458–62.

    CAS  PubMed  Google Scholar 

  4. 4.

    Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.

    CAS  PubMed  Google Scholar 

  7. 7.

    Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.

    CAS  PubMed  Google Scholar 

  8. 8.

    Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352–60.

    CAS  PubMed  Google Scholar 

  10. 10.

    Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378:2465–74.

    CAS  PubMed  Google Scholar 

  11. 11.

    Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235–46.

    CAS  PubMed  Google Scholar 

  12. 12.

    Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408–18.

    CAS  PubMed  Google Scholar 

  13. 13.

    Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY Study. J Clin Oncol. 2019;37:1120–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Khalaf DJ, Annala M, Taavitsainen S, Finch DL, Oja C, Vergidis J, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20:1730–9.

    CAS  PubMed  Google Scholar 

  15. 15.

    Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE Trial. J Clin Oncol. 2016;34:2098–106.

    CAS  PubMed  Google Scholar 

  16. 16.

    Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, Liu G, et al. Phase 2 study of the safety and antitumor activity of apalutamide (ARN-509), a potent androgen receptor antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol. 2016;70:963–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Fizazi K, Massard C, Bono P, Kataja V, James N, Tammela TL, et al. Safety and antitumour activity of ODM-201 (BAY-1841788) in castration-resistant, CYP17 Inhibitor-naive prostate cancer: results from extended follow-up of the ARADES Trial. Eur Urol focus. 2017;3:606–14.

    PubMed  Google Scholar 

  18. 18.

    James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20:686–700.

    CAS  PubMed  Google Scholar 

  20. 20.

    Ryan CJ, Crawford ED, Shore ND, Underwood W 3rd, Taplin ME, Londhe A, et al. The IMAAGEN Study: effect of abiraterone acetate and prednisone on prostate specific antigen and radiographic disease progression in patients with nonmetastatic castration resistant prostate cancer. J Urol. 2018;200:344–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019;30:1813–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Tombal B, Saad F, Penson D, Hussain M, Sternberg CN, Morlock R, et al. Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20:556–69.

    CAS  PubMed  Google Scholar 

  23. 23.

    Lu C, Luo J. Decoding the androgen receptor splice variants. Transl Androl Urol. 2013;2:178–86.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis. 2016;19:231–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Luo J, Attard G, Balk SP, Bevan C, Burnstein K, Cato L, et al. Role of androgen receptor variants in prostate cancer: report from the 2017 Mission Androgen Receptor Variants Meeting. Eur Urol. 2018;73:715–23.

    PubMed  Google Scholar 

  26. 26.

    Ware KE, Garcia-Blanco MA, Armstrong AJ, Dehm SM. Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer. Endocr Relat Cancer. 2014;21:T87–T103.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1:582–91.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Lokhandwala PM, Riel SL, Haley L, Lu C, Chen Y, Silberstein J, et al. Analytical validation of androgen receptor splice variant 7 detection in a Clinical Laboratory Improvement Amendments (CLIA) Laboratory Setting. J Mol Diagn. 2017;19:115–25.

    CAS  PubMed  Google Scholar 

  29. 29.

    Markowski MC, Silberstein JL, Eshleman JR, Eisenberger MA, Luo J, Antonarakis ES. Clinical utility of CLIA-Grade AR-V7 testing in patients with metastatic castration-resistant prostate cancer. JCO Precis Oncol. 2017;1:1–9.

    Google Scholar 

  30. 30.

    Taplin ME, Antonarakis ES, Ferrante KJ, Horgan K, Blumenstein B, Saad F, et al. Androgen receptor modulation optimized for response-splice variant: a phase 3, randomized trial of galeterone versus enzalutamide in androgen receptor splice variant-7-expressing metastatic castration-resistant prostate cancer. Eur Urol. 2019;76:843–51.

    CAS  PubMed  Google Scholar 

  31. 31.

    Miyamoto DT, Lee RJ, Kalinich M, LiCausi JA, Zheng Y, Chen T, et al. An RNA-based digital circulating tumor cell signature is predictive of drug response and early dissemination in prostate cancer. Cancer Discov. 2018;8:288–303.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Ma Y, Luk A, Young FP, Lynch D, Chua W, Balakrishnar B, et al. Droplet digital PCR based androgen receptor variant 7 (AR-V7) detection from prostate cancer patient blood biopsies. Int J Mol Sci. 2016;17:E1264.

    PubMed  Google Scholar 

  33. 33.

    Markou A, Lazaridou M, Paraskevopoulos P, Chen S, Swierczewska M, Budna J, et al. Multiplex gene expression profiling of in vivo isolated circulating tumor cells in high-risk prostate cancer patients. Clin Chem. 2018;64:297–306.

    CAS  PubMed  Google Scholar 

  34. 34.

    El-Heliebi A, Hille C, Laxman N, Svedlund J, Haudum C, Ercan E, et al. In situ detection and quantification of AR-V7, AR-FL, PSA, and KRAS point mutations in circulating tumor cells. Clin Chem. 2018;64:536–46.

    CAS  PubMed  Google Scholar 

  35. 35.

    Theil G, Fischer K, Weber E, Medek R, Hoda R, Lucke K, et al. The use of a new CellCollector to isolate circulating tumor cells from the blood of patients with different stages of prostate cancer and clinical outcomes—a proof-of-concept study. PLoS ONE. 2016;11:e0158354.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Vermesh O, Aalipour A, Ge TJ, Saenz Y, Guo Y, Alam IS, et al. An intravascular magnetic wire for the high-throughput retrieval of circulating tumour cells in vivo. Nat Biomed Eng. 2018;2:696–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Skerenova M, Mikulova V, Capoun O, Svec D, Kolostova K, Soukup V, et al. Gene expression analysis of immunomagnetically enriched circulating tumor cell fraction in castration-resistant prostate cancer. Mol Diagn Ther. 2018;22:381–90.

    CAS  PubMed  Google Scholar 

  38. 38.

    Seitz AK, Thoene S, Bietenbeck A, Nawroth R, Tauber R, Thalgott M, et al. AR-V7 in peripheral whole blood of patients with castration-resistant prostate cancer: association with treatment-specific outcome under abiraterone and enzalutamide. Eur Urol. 2017;72:828–34.

    CAS  PubMed  Google Scholar 

  39. 39.

    Todenhofer T, Azad A, Stewart C, Gao J, Eigl BJ, Gleave ME, et al. AR-V7 transcripts in whole blood RNA of patients with metastatic castration resistant prostate cancer correlate with response to abiraterone acetate. J Urol. 2017;197:135–42.

    CAS  PubMed  Google Scholar 

  40. 40.

    Liu X, Ledet E, Li D, Dotiwala A, Steinberger A, Feibus A, et al. A whole blood assay for AR-V7 and AR(v567es) in patients with prostate cancer. J Urol. 2016;196:1758–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Takeuchi T, Okuno Y, Hattori-Kato M, Zaitsu M, Mikami K. Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer. Res Rep Urol. 2016;8:21–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Walecki M, Eisel F, Klug J, Baal N, Paradowska-Dogan A, Wahle E, et al. Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells. Mol Biol Cell. 2015;26:2845–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Ashcroft GS, Mills SJ. Androgen receptor-mediated inhibition of cutaneous wound healing. f. 2002;110:615–24.

    CAS  Google Scholar 

  44. 44.

    Del ReM, Biasco E, Crucitta S, Derosa L, Rofi E, Orlandini C, et al. The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients. Eur Urol. 2017;71:680–7.

    Google Scholar 

  45. 45.

    Woo HK, Park J, Ku JY, Lee CH, Sunkara V, Ha HK, et al. Urine-based liquid biopsy: non-invasive and sensitive AR-V7 detection in urinary EVs from patients with prostate cancer. Lab Chip. 2018;19:87–97.

    PubMed  Google Scholar 

  46. 46.

    Guedes LB, Morais CL, Almutairi F, Haffner MC, Zheng Q, Isaacs JT, et al. Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer. Clin Cancer Res. 2016;22:4651–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Saylor PJ, Lee RJ, Arora KS, Deshpande V, Hu R, Olivier K, et al. Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer. Clin Cancer Res. 2017;23:363–9.

    CAS  PubMed  Google Scholar 

  48. 48.

    Zhu Y, Sharp A, Anderson CM, Silberstein JL, Taylor M, Lu C, et al. Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2018;73:727–35.

    CAS  PubMed  Google Scholar 

  49. 49.

    Scher HI, Graf RP, Schreiber NA, McLaughlin B, Lu D, Louw J, et al. Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2017;71:874–82.

    CAS  PubMed  Google Scholar 

  50. 50.

    Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J Clin Investig. 2019;129:192–208.

    PubMed  Google Scholar 

  51. 51.

    Welti J, Rodrigues DN, Sharp A, Sun S, Lorente D, Riisnaes R, et al. Analytical validation and clinical qualification of a new immunohistochemical assay for androgen receptor splice variant-7 protein expression in metastatic castration-resistant prostate cancer. Eur Urol. 2016;70:599–608.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Zhao P, Zhu Y, Cheng L, Luo J. Detection of androgen receptor (AR) and AR-V7 in small cell prostate carcinoma: diagnostic and therapeutic implications. Asian J Urol. 2019;6:109–13.

    PubMed  Google Scholar 

  53. 53.

    Li H, Wang Z, Xiao W, Yan L, Guan W, Hu Z, et al. Androgen-receptor splice variant-7-positive prostate cancer: a novel molecular subtype with markedly worse androgen-deprivation therapy outcomes in newly diagnosed patients. Mod Pathol. 2018;31:198–208.

    CAS  PubMed  Google Scholar 

  54. 54.

    Scher HI, Graf RP, Schreiber NA, Jayaram A, Winquist E, McLaughlin B, et al. Assessment of the validity of nuclear-localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration-resistant prostate cancer. JAMA Oncol. 2018;4:1179–86.

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, et al. Clinical utility of circulating tumour cell androgen receptor splice variant-7 status in metastatic castration-resistant prostate cancer. Eur Urol. 2019;76:676–85.

    CAS  PubMed  Google Scholar 

  56. 56.

    Yang RK, Zhao P, Lu C, Luo J, Hu R. Expression pattern of androgen receptor and AR-V7 in androgen-deprivation therapy-naive salivary duct carcinomas. Hum Pathol. 2019;84:173–82.

    CAS  PubMed  Google Scholar 

  57. 57.

    Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;162:454.

    CAS  PubMed  Google Scholar 

  58. 58.

    Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

    Google Scholar 

  60. 60.

    Henzler C, Li Y, Yang R, McBride T, Ho Y, Sprenger C, et al. Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nat Commun. 2016;7:13668.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    De Laere B, van Dam PJ, Whitington T, Mayrhofer M, Diaz EH, Van den Eynden G, et al. Comprehensive profiling of the androgen receptor in liquid biopsies from castration-resistant prostate cancer reveals novel intra-AR structural variation and splice variant expression patterns. Eur Urol. 2017;72:192–200.

    PubMed  Google Scholar 

  62. 62.

    Kallio HML, Hieta R, Latonen L, Brofeldt A, Annala M, Kivinummi K, et al. Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases. Br J Cancer. 2018;119:347–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Kohli M, Ho Y, Hillman DW, Van Etten JL, Henzler C, Yang R, et al. Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance. Clin Cancer Res. 2017;23:4704–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72:3457–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, Dong X. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 2014;33:3140–50.

    CAS  PubMed  Google Scholar 

  66. 66.

    Nakata D, Nakayama K, Masaki T, Tanaka A, Kusaka M, Watanabe T. Growth inhibition by testosterone in an androgen receptor splice variant-driven prostate cancer model. Prostate. 2016;76:1536–45.

    CAS  PubMed  Google Scholar 

  67. 67.

    Teply BA, Wang H, Luber B, Sullivan R, Rifkind I, Bruns A, et al. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2018;19:76–86.

    CAS  PubMed  Google Scholar 

  68. 68.

    Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA. 2010;107:16759–65.

    CAS  PubMed  Google Scholar 

  69. 69.

    Yu Z, Chen S, Sowalsky AG, Voznesensky OS, Mostaghel EA, Nelson PS, et al. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res. 2014;20:1590–1600.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Zhu Y, Luo J. Regulation of androgen receptor variants in prostate cancer. Asian J Urol. 2020.

  71. 71.

    Nadiminty N, Tummala R, Liu C, Lou W, Evans CP, Gao AC. NF-kappaB2/p52:c-Myc:hnRNPA1 pathway regulates expression of androgen receptor splice variants and enzalutamide sensitivity in prostate cancer. Mol Cancer Ther. 2015;14:1884–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Zhang Z, Zhou N, Huang J, Ho TT, Zhu Z, Qiu Z, et al. Regulation of androgen receptor splice variant AR3 by PCGEM1. Oncotarget. 2016;7:15481–91.

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Ho TT, Huang J, Zhou N, Zhang Z, Koirala P, Zhou X, et al. Regulation of PCGEM1 by p54/nrb in prostate cancer. Sci Rep. 2016;6:34529.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Wang B, Lo UG, Wu K, Kapur P, Liu X, Huang J, et al. Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer. Int J Cancer. 2017;141:2121–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Fan L, Zhang F, Xu S, Cui X, Hussain A, Fazli L, et al. Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells. Proc Natl Acad Sci USA. 2018;115:E4584–93.

    CAS  PubMed  Google Scholar 

  76. 76.

    Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. 2006;125:483–95.

    CAS  PubMed  Google Scholar 

  77. 77.

    Fan L, Peng G, Sahgal N, Fazli L, Gleave M, Zhang Y, et al. Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival. Oncogene. 2016;35:2441–52.

    CAS  PubMed  Google Scholar 

  78. 78.

    Wilson S, Fan L, Sahgal N, Qi J, Filipp FV. The histone demethylase KDM3A regulates the transcriptional program of the androgen receptor in prostate cancer cells. Oncotarget. 2017;8:30328–43.

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Nakata D, Nakao S, Nakayama K, Araki S, Nakayama Y, Aparicio S, et al. The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation. Biochem Biophys Res Commun. 2017;483:271–6.

    CAS  PubMed  Google Scholar 

  80. 80.

    Tummala R, Nadiminty N, Lou W, Evans CP, Gao AC. Lin28 induces resistance to anti-androgens via promotion of AR splice variant generation. Prostate. 2016;76:445–55.

    CAS  PubMed  Google Scholar 

  81. 81.

    Wang R, Sun Y, Li L, Niu Y, Lin W, Lin C, et al. Preclinical study using Malat1 small interfering RNA or androgen receptor splicing variant 7 degradation enhancer ASC-J9((R)) to suppress enzalutamide-resistant prostate cancer progression. Eur Urol. 2017;72:835–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Szafran AT, Stephan C, Bolt M, Mancini MG, Marcelli M, Mancini MA. High-content screening identifies Src family kinases as potential regulators of AR-V7 expression and androgen-independent cell growth. Prostate. 2017;77:82–93.

    CAS  PubMed  Google Scholar 

  83. 83.

    Mahajan K, Malla P, Lawrence HR, Chen Z, Kumar-Sinha C, Malik R, et al. ACK1/TNK2 regulates histone H4 Tyr88-phosphorylation and AR gene expression in castration-resistant prostate cancer. Cancer Cell. 2017;31:790–803.e798.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Shiota M, Fujimoto N, Imada K, Yokomizo A, Itsumi M, Takeuchi A, et al. Potential role for YB-1 in castration-resistant prostate cancer and resistance to enzalutamide through the androgen receptor V7. J Natl Cancer Inst. 2016;108:1–10.

    Google Scholar 

  85. 85.

    Udayakumar TS, Stoyanova R, Shareef MM, Mu Z, Philip S, Burnstein KL, et al. Edelfosine promotes apoptosis in androgen-deprived prostate tumors by increasing ATF3 and inhibiting androgen receptor activity. Mol Cancer Ther. 2016;15:1353–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Wang J, Zou JX, Xue X, Cai D, Zhang Y, Duan Z, et al. ROR-gamma drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nat Med. 2016;22:488–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Wu G, Sun Y, Xiang Z, Wang K, Liu B, Xiao G, et al. Preclinical study using circular RNA 17 and micro RNA 181c-5p to suppress the enzalutamide-resistant prostate cancer progression. Cell Death Dis. 2019;10:37.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Cai L, Tsai YH, Wang P, Wang J, Li D, Fan H, et al. ZFX mediates non-canonical oncogenic functions of the androgen receptor splice variant 7 in castrate-resistant prostate cancer. Mol Cell. 2018;72:341–54.e346.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Chen Z, Wu D, Thomas-Ahner JM, Lu C, Zhao P, Zhang Q, et al. Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proc Natl Acad Sci USA. 2018;115:6810–5.

    CAS  PubMed  Google Scholar 

  90. 90.

    Cato L, de Tribolet-Hardy J, Lee I, Rottenberg JT, Coleman I, Melchers D, et al. ARv7 represses tumor-suppressor genes in castration-resistant prostate cancer. Cancer Cell. 2019;35:401–13.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    He Y, Lu J, Ye Z, Hao S, Wang L, Kohli M, et al. Androgen receptor splice variants bind to constitutively open chromatin and promote abiraterone-resistant growth of prostate cancer. Nucleic Acids Res. 2018;46:1895–911.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Cai C, He HH, Chen S, Coleman I, Wang H, Fang Z, et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell. 2011;20:457–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Cao B, Qi Y, Zhang G, Xu D, Zhan Y, Alvarez X, et al. Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget. 2014;5:1646–56.

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Xu D, Zhan Y, Qi Y, Cao B, Bai S, Xu W, et al. Androgen receptor splice variants dimerize to transactivate target genes. Cancer Res. 2015;75:3663–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Purushottamachar P, Kwegyir-Afful AK, Martin MS, Ramamurthy VP, Ramalingam S, Njar VC. Identification of novel steroidal androgen receptor degrading agents inspired by galeterone 3beta-imidazole carbamate. ACS Med Chem Lett. 2016;7:708–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Yang YC, Banuelos CA, Mawji NR, Wang J, Kato M, Haile S, et al. Targeting androgen receptor activation function-1 with EPI to overcome resistance mechanisms in castration-resistant prostate cancer. Clin Cancer Res. 2016;22:4466–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Brand LJ, Olson ME, Ravindranathan P, Guo H, Kempema AM, Andrews TE, et al. EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer. Oncotarget. 2015;6:3811–24.

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Shimizu Y, Tamada S, Kato M, Hirayama Y, Takeyama Y, Iguchi T, et al. Androgen receptor splice variant 7 drives the growth of castration resistant prostate cancer without being involved in the efficacy of taxane chemotherapy. J Clin Med. 2018;7:E444.

    PubMed  Google Scholar 

  99. 99.

    Moigne RL, Banuelos CA, Mawji NR, Tam T, Wang J, Jian K, et al. EPI-7386 is a novel N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer. Ann Oncol. 2019;30(Suppl 5):v159–93.

    Google Scholar 

  100. 100.

    Goicochea NL, Garnovskaya M, Blanton MG, Chan G, Weisbart R, Lilly MB. Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy. Protein Eng Des Sel. 2017;30:785–93.

    PubMed  Google Scholar 

  101. 101.

    Lai KP, Huang CK, Chang YJ, Chung CY, Yamashita S, Li L, et al. New therapeutic approach to suppress castration-resistant prostate cancer using ASC-J9 via targeting androgen receptor in selective prostate cells. Am J Pathol. 2013;182:460–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Cheng MA, Chou FJ, Wang K, Yang R, Ding J, Zhang Q, et al. Androgen receptor (AR) degradation enhancer ASC-J9((R)) in an FDA-approved formulated solution suppresses castration resistant prostate cancer cell growth. Cancer Lett. 2018;417:182–91.

    CAS  PubMed  Google Scholar 

  103. 103.

    Li H, Hassona MD, Lack NA, Axerio-Cilies P, Leblanc E, Tavassoli P, et al. Characterization of a new class of androgen receptor antagonists with potential therapeutic application in advanced prostate cancer. Mol Cancer Ther. 2013;12:2425–35.

    CAS  PubMed  Google Scholar 

  104. 104.

    Dalal K, Morin H, Ban F, Shepherd A, Fernandez M, Tam KJ, et al. Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor. Eur J Med Chem. 2018;157:1164–73.

    CAS  PubMed  Google Scholar 

  105. 105.

    Ponnusamy S, Coss CC, Thiyagarajan T, Watts K, Hwang DJ, He Y, et al. Novel selective agents for the degradation of androgen receptor variants to treat castration-resistant prostate cancer. Cancer Res. 2017;77:6282–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Hwang DJ, He Y, Ponnusamy S, Mohler ML, Thiyagarajan T, McEwan IJ, et al. New generation of selective androgen receptor degraders: our initial design, synthesis, and biological evaluation of new compounds with enzalutamide-resistant prostate cancer activity. J Med Chem. 2019;62:491–511.

    CAS  PubMed  Google Scholar 

  107. 107.

    Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs. Pharm Ther. 2017;174:138–44.

    CAS  Google Scholar 

  108. 108.

    Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews CM, Deshaies RJ, et al. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene. 2008;27:7201–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Han X, Wang C, Qin C, Xiang W, Fernandez-Salas E, Yang CY, et al. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of androgen receptor (AR) for the treatment of prostate cancer. J Med Chem. 2019;62:941–64.

    CAS  PubMed  Google Scholar 

  110. 110.

    Salami J, Alabi S, Willard RR, Vitale NJ, Wang J, Dong H, et al. Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol. 2018;1:100.

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Neklesa T, Snyder LB, Willard RR, Vitale N, Pizzano J, Gordon DA, et al. ARV-110: an oral androgen receptor PROTAC degrader for prostate cancer. J Clin Oncol. 2019;37(Suppl 7):259–259.

    Google Scholar 

  112. 112.

    Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2016;113:7124–9.

    CAS  PubMed  Google Scholar 

  113. 113.

    Zhang X, Castanotto D, Nam S, Horne D, Stein C. 6BIO enhances oligonucleotide activity in cells: a potential combinatorial anti-androgen receptor therapy in prostate cancer cells. Mol Ther. 2017;25:79–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Wadosky KM, Shourideh M, Goodrich DW, Koochekpour S. Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen-dependent and castration-resistant prostate cancer cells. Prostate. 2019;79:140–50.

    CAS  PubMed  Google Scholar 

  115. 115.

    Singh KB, Ji X, Singh SV. Therapeutic potential of leelamine, a novel inhibitor of androgen receptor and castration-resistant prostate cancer. Mol Cancer Ther. 2018;17:2079–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Moses MA, Kim YS, Rivera-Marquez GM, Oshima N, Watson MJ, Beebe KE, et al. Targeting the Hsp40/Hsp70 chaperone axis as a novel strategy to treat castration-resistant prostate cancer. Cancer Res. 2018;78:4022–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Kita K, Shiota M, Tanaka M, Otsuka A, Matsumoto M, Kato M, et al. Heat shock protein 70 inhibitors suppress androgen receptor expression in LNCaP95 prostate cancer cells. Cancer Sci. 2017;108:1820–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Ferraldeschi R, Welti J, Powers MV, Yuan W, Smyth T, Seed G, et al. Second-generation HSP90 inhibitor onalespib blocks mRNA splicing of androgen receptor variant 7 in prostate cancer cells. Cancer Res. 2016;76:2731–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, et al. Targeting bromodomain and extra-terminal (BET) family proteins in castration-resistant prostate cancer (CRPC). Clin Cancer Res. 2018;24:3149–62.

    CAS  PubMed  Google Scholar 

  120. 120.

    Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Yang L, Zhang Y, Shan W, Hu Z, Yuan J, Pi J, et al. Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med. 2017;9:eaal1645.

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Zhang P, Wang D, Zhao Y, Ren S, Gao K, Ye Z, et al. Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat Med. 2017;23:1055–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Dai X, Gan W, Li X, Wang S, Zhang W, Huang L, et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med. 2017;23:1063–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Malvaez M, McQuown SC, Rogge GA, Astarabadi M, Jacques V, Carreiro S, et al. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci USA. 2013;110:2647–52.

    CAS  PubMed  Google Scholar 

  125. 125.

    McLeod AB, Stice JP, Wardell SE, Alley HM, Chang CY, McDonnell DP. Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer. Prostate. 2018;78:266–77.

    CAS  PubMed  Google Scholar 

  126. 126.

    Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.

    CAS  PubMed  Google Scholar 

  127. 127.

    Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Kim J, Lee Y, Lu X, Song B, Fong KW, Cao Q, et al. Polycomb- and methylation-independent roles of EZH2 as a transcription activator. Cell Rep. 2018;25:2808–20.e2804.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Wu C, Jin X, Yang J, Yang Y, He Y, Ding L, et al. Inhibition of EZH2 by chemo- and radiotherapy agents and small molecule inhibitors induces cell death in castration-resistant prostate cancer. Oncotarget. 2016;7:3440–52.

    PubMed  Google Scholar 

  130. 130.

    Murashima A, Shinjo K, Katsushima K, Onuki T, Kondoh Y, Osada H, et al. Identification of a chemical modulator of EZH2-mediated silencing by cell-based high-throughput screening assay. J Biochem. 2019;166:41–50.

    CAS  PubMed  Google Scholar 

  131. 131.

    Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355:78–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Ma L, Yan Y, Bai Y, Yang Y, Pan Y, Gang X, et al. Overcoming EZH2 inhibitor resistance by taxane in PTEN-Mutated cancer. Theranostics. 2019;9:5020–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Liu Q, Wang G, Li Q, Jiang W, Kim JS, Wang R, et al. Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer. Int J Cancer. 2019;145:415–26.

    CAS  PubMed  Google Scholar 

  134. 134.

    Lai CJ, Bao R, Tao X, Wang J, Atoyan R, Qu H, et al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res. 2010;70:3647–56.

    CAS  PubMed  Google Scholar 

  135. 135.

    Sun H, Mediwala SN, Szafran AT, Mancini MA, Marcelli M. CUDC-101, a novel inhibitor of full-length androgen receptor (flAR) and androgen receptor variant 7 (AR-V7) activity: mechanism of action and in vivo efficacy. Horm Cancer. 2016;7:196–210.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Ianculescu I, Wu DY, Siegmund KD, Stallcup MR. Selective roles for cAMP response element-binding protein binding protein and p300 protein as coregulators for androgen-regulated gene expression in advanced prostate cancer cells. J Biol Chem. 2012;287:4000–13.

    CAS  PubMed  Google Scholar 

  137. 137.

    Heemers HV, Sebo TJ, Debes JD, Regan KM, Raclaw KA, Murphy LM, et al. Androgen deprivation increases p300 expression in prostate cancer cells. Cancer Res. 2007;67:3422–30.

    CAS  PubMed  Google Scholar 

  138. 138.

    Jin L, Garcia J, Chan E, de la Cruz C, Segal E, Merchant M, et al. Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of castration-resistant prostate cancer. Cancer Res. 2017;77:5564–75.

    CAS  PubMed  Google Scholar 

  139. 139.

    Pegg N, Brooks N, Worthington J, Young B, Prosser A, Lane J, et al. Characterisation of CCS1477: a novel small molecule inhibitor of p300/CBP for the treatment of castration resistant prostate cancer. J Clin Oncol. 2017;35(Suppl 15):11590–11590.

    Google Scholar 

  140. 140.

    Yan Y, Ma J, Wang D, Lin D, Pang X, Wang S, et al. The novel BET-CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer. EMBO Mol Med. 2019;11:e10659.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Butler L, Irani S, Centenera M, Ryan N, Pegg N, Brooks AN. Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants. J Clin Oncol. 2019;37 (Suppl 15):e16534–e16534.

    Google Scholar 

  142. 142.

    Stice JP, Wardell SE, Norris JD, Yllanes AP, Alley HM, Haney VO, et al. CDK4/6 therapeutic intervention and viable alternative to taxanes in CRPC. Mol Cancer Res. 2017;15:660–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Kivinummi K, Urbanucci A, Leinonen K, Tammela TLJ, Annala M, Isaacs WB, et al. The expression of AURKA is androgen regulated in castration-resistant prostate cancer. Sci Rep. 2017;7:17978.

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Jones D, Noble M, Wedge SR, Robson CN, Gaughan L. Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer. Sci Rep. 2017;7:40957.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Sarkar S, Brautigan DL, Larner JM. Aurora kinase A promotes AR degradation via the E3 ligase CHIP. Mol Cancer Res. 2017;15:1063–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Beltran H, Oromendia C, Danila DC, Montgomery B, Hoimes C, Szmulewitz RZ, et al. A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration-resistant and neuroendocrine prostate cancer: efficacy and biomarkers. Clin Cancer Res. 2019;25:43–51.

    CAS  PubMed  Google Scholar 

  147. 147.

    Titov DV, Gilman B, He QL, Bhat S, Low WK, Dang Y, et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol. 2011;7:182–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Chugh R, Sangwan V, Patil SP, Dudeja V, Dawra RK, Banerjee S, et al. A preclinical evaluation of minnelide as a therapeutic agent against pancreatic cancer. Sci Transl Med. 2012;4:156ra139.

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Isharwal S, Modi S, Arora N, Uhlrich C 3rd, Giri B, Barlass U, et al. Minnelide inhibits androgen dependent, castration resistant prostate cancer growth by decreasing expression of androgen receptor full length and splice variants. Prostate. 2017;77:584–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Rosati R, Patki M, Chari V, Dakshnamurthy S, McFall T, Saxton J, et al. The amino-terminal domain of the androgen receptor co-opts extracellular signal-regulated kinase (ERK) docking sites in ELK1 protein to induce sustained gene activation that supports prostate cancer cell growth. J Biol Chem. 2016;291:25983–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Rosati R, Polin L, Ducker C, Li J, Bao X, Selvakumar D, et al. Strategy for tumor-selective disruption of androgen receptor function in the spectrum of prostate cancer. Clin Cancer Res. 2018;24:6509–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Gaur S, Gross ME, Liao CP, Qian B, Shih JC. Effect of monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells. Prostate. 2019;79:667–77.

    CAS  PubMed  Google Scholar 

  153. 153.

    Zadra G, Ribeiro CF, Chetta P, Ho Y, Cacciatore S, Gao X, et al. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2019;116:631–40.

    CAS  PubMed  Google Scholar 

  154. 154.

    Nakata D, Koyama R, Nakayama K, Kitazawa S, Watanabe T, Hara T. Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells. Prostate. 2017;77:955–61.

    CAS  PubMed  Google Scholar 

  155. 155.

    Magani F, Bray ER, Martinez MJ, Zhao N, Copello VA, Heidman L, et al. Identification of an oncogenic network with prognostic and therapeutic value in prostate cancer. Mol Syst Biol. 2018;14:e8202.

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Recouvreux MV, Wu JB, Gao AC, Zonis S, Chesnokova V, Bhowmick N, et al. Androgen receptor regulation of local growth hormone in prostate cancer cells. Endocrinology. 2017;158:2255–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Ramamurthy VP, Ramalingam S, Gediya LK, Njar VCO. The retinamide VNLG-152 inhibits f-AR/AR-V7 and MNK-eIF4E signaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth. FEBS J. 2018;285:1051–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Ramamurthy VP, Ramalingam S, Gediya L, Kwegyir-Afful AK, Njar VC. Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines. Oncotarget. 2015;6:3195–210.

    PubMed  Google Scholar 

  159. 159.

    Li D, Tian G, Wang J, Zhao LY, Co O, Underill ZC, et al. Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival. Prostate. 2018;78:1140–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Nunes JJ, Pandey SK, Yadav A, Goel S, Ateeq B. Targeting NF-kappa B signaling by artesunate restores sensitivity of castrate-resistant prostate cancer cells to antiandrogens. Neoplasia. 2017;19:333–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Dyshlovoy SA, Menchinskaya ES, Venz S, Rast S, Amann K, Hauschild J, et al. The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer. Int J Cancer. 2016;138:2450–65.

    CAS  PubMed  Google Scholar 

Download references


ESA has received funding from the Prostate Cancer Foundation, the Patrick C. Walsh Fund, and NIH grants R01 CA185297 and P30 CA006973. AJA has received funding from a Prostate Cancer Foundation and Movember Global Treatment Sciences Challenge Award and the NIH under a P30 CA014236 and 1R01CA233585-01 grant. JL is currently funded by a Prostate Cancer Foundation grant, NIH grant R01 CA185297, and US Department of Defense Prostate Cancer Research Program grant W81XWH-19-1-0686.

Author information



Corresponding author

Correspondence to Jun Luo.

Ethics declarations

Conflict of interest

ESA has served as a paid consultant/advisor for Janssen, Pfizer, Sanofi, Dendreon, Essa, Merck, Bristol-Myers Squibb, AstraZeneca, Clovis, Eli Lilly, and Amgen; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Merck, Bristol-Myers Squibb, AstraZeneca, and Constellation; and is a co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. AJA has served as a paid consultant for AstraZeneca, Merck, Dendreon, Janssen, Clovis, Bayer, and Medivation/Astellas; is on the speaker’s bureau for Bayer and Dendreon; and receives research funding to his institution from Janssen, Medivation/Astellas, Sanofi-Aventis, Active Biotech, Bayer, Dendreon, Merck, AstraZeneca, Genentech/Roche, BMS, Constellation, Novartis, and Pfizer. JL has served as a paid consultant/advisor for Sun Pharma, Janssen, Tolero, and Sanofi; has received research funding to his institution from Orion, Mirati, Astellas, Sanofi, Constellation, Calibr, Pandomedx, and Gilead; and is a co-inventor of a technology that has been licensed to Tokai, Qiagen, and A&G. CL is a co-inventor of a technology that has been licensed to Tokai and Qiagen.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lu, C., Brown, L.C., Antonarakis, E.S. et al. Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations. Prostate Cancer Prostatic Dis 23, 381–397 (2020).

Download citation