• What is AR?
  • AR in Prostate Cancer
  • AR Splice Variant 7 (AR-V7) Expression
  • Clinical Trials


The androgen receptor (AR) plays a role in the pathogenesis of prostate cancer and can be expressed in invasive breast cancer (Itkonen and Mills 2012; Gonzalez et al 2008). AR is the product of the AR gene, which is located on the X chromosome. AR is in the nuclear receptor superfamily and is part of the steroid receptor family, and it has a six-region structure with a defined functional domain (Itkonen and Mills 2012).

Amplification of the AR gene and AR mutations occur in 30% and 1-30% of castration-resistant prostate cancer, respectively (Waltering et al. 2012). AR expression is measured using immunohistochemistry (IHC), and is detectable in the majority of castration-resistant prostate cancer (Linja et al. 2001; Waltering et al. 2012) and 75% of invasive breast cancers (Collins et al. 2011; Gonzalez et al 2008).

Related Pathways

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2016. AR. My Cancer Genome https://www.padiracinnovation.org/content/disease/prostate-cancer/ar/?tab=0 (Updated September 12).

Last Updated: September 12, 2016

AR (AR) in Prostate Cancer

Targeting the androgen receptor (AR) pathway is the primary focus of most prostate cancer therapeutics. AR signaling is important for the normal development and function of the prostate gland and also plays a clear role in the development and progression of nearly all primary malignancies of the prostate (Lonergan and Tindall 2011; Tan et al. 2015). Androgen deprivation therapy, through surgical or pharmacological castration, has been the primary treatment for prostate cancer for nearly 70 years and is successful at inducing tumor regressions in most patients (Huggins and Hodges 1941; Huggins et al. 1941). However, given long enough, nearly all patients will progress on these therapies to metastatic castration-resistant prostate cancer (mCRPC), an ultimately lethal disease that is no longer sensitive to first-line androgen deprivation therapies (Tan et al. 2015; Watson et al. 2015).

It is now well recognized that mCRPC remains driven by AR signaling (Chen et al. 2004; Watson et al. 2015), and this can occur through both ligand-dependent and ligand-independent means. Mechanisms capable of maintaining AR signaling include tumoral or extragonadal sources of androgens, AR amplification, overexpression, mutations, splice variants, and/or reactivation of the AR through bypass or crosstalk pathways (Graham and Schweizer 2016; Lonergan and Tindall 2011; Watson et al. 2015). Therapeutic strategies to more potently target the AR through AR antagonism (e.g., enzalutamide) or inhibition of androgen synthesis (e.g., abiraterone acetate) have been shown to extend patient survival in randomized Phase 3 clinical trials for patients with CRPC, and these drugs are now in widespread clinical use. However, intrinsic and acquired resistance to these newer more potent AR drugs remains a significant challenge. In most cases, resistance continues to be driven by AR signaling (Imamura and Sadar 2016; Watson et al. 2015), which has led to the development of novel AR-targeting drugs and combination therapies. A subset of CRPC cases may lose dependence on AR signaling, which is often associated with low or absent AR expression and the development of neuroendocrine features (Beltran et al. 2012; Beltran et al. 2016).

The mechanisms underlying primary and acquired resistance to antiandrogen therapies and the role of the AR gene, the AR transcript, and/or the AR protein product are incompletely elucidated. Understanding how AR variations contribute to response and resistance may have prognostic or predictive value towards improving the clinical management of patients with mCRPC (Daniel and Dehm 2016).

Clinical case series combined with supporting preclinical data have suggested that AR amplification, AR overexpression, mutations involving the ligand-binding domain, and AR splice variants are associated with primary and/or acquired resistance to second-generation antiandrogen therapies for mCRPC (Antonarakis et al. 2014; Azad et al. 2015; Carreira et al. 2014; Romanel et al. 2015; Wyatt et al. 2016). Together, AR aberrations are found in ~60% of mCRPC; AR mutations are found in 15–20% of mCRPC cases, and AR copy number gains or amplifications are found in 25–50% (Beltran et al. 2013; Robinson et al. 2015). A recent study reported that patients with a single AR mutation did not exhibit primary resistance to enzalutamide but that patients with multiple AR mutations or amplification showed a worsened progression-free survival, indicative of resistance (Wyatt et al. 2016).

Taxane chemotherapies are also commonly used for the treatment of patients with mCRPC, with docetaxel approved by the FDA in 2004 and cabazitaxel approved in the second line in 2010. Taxanes act through microtubule stabilization, though have also been reported to inhibit AR signaling in mCRPC through suppressed nuclear translocation of the AR protein (Imamura and Sadar 2016). The AR hinge region is important for this effect, and preclinical data suggest that AR splice variants lacking the AR hinge region (e.g., AR-V7) are less sensitive to these therapies (Imamura and Sadar 2016). While expression of AR-V7 has been associated with resistance to abiraterone and enzalutamide, this has not been observed with taxanes (Antonarakis et al. 2015); therefore AR-V7 may represent a treatment selection biomarker. These findings are now undergoing further prospective validation and clinical qualification.

Novel strategies that target (1) the AR N-terminal domain, which is constitutively active in absence of the ligand-binding domain, (2) the AR DNA-binding domain, to diminish AR target gene transcription, (3) co-regulators of the AR pathway, (4) multimodal AR pathway components, or (5) AR variants associated with therapeutic resistance are currently under development along with new antiandrogens (Bambury and Rathkopf 2015; Crona et al. 2015; Culig and Santer 2014; Graham and Schweizer 2016; Imamura and Sadar 2016; Tan et al. 2015).

Contributors: Himisha Beltran, M.D.

Suggested Citation: Beltran, H. 2016. AR (AR) in Prostate Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/prostate-cancer/ar/ (Updated September 12).

Last Updated: September 12, 2016

AR Splice Variant 7 (AR-V7) Expression in Prostate Cancer

Structure of variant Contains exons 1–3 followed by novel C-terminal cryptic exon 3
Protein expressed? Yes
Frequency of AR-V7 expression in castration-resistant prostate cancer Not well establisheda
Implications for Targeted Therapeutics
Response to hydroxyflutamide Unknown at this time
Response to bicalutamide Unknown at this time
Response to enzalutamide Unknown at this timeb
Response to abiraterone Unknown at this timec
Response to novel targeted therapies Unknown at this timed
Response to other therapies Unknown at this timee

AR is alternatively spliced in normal prostate tissue (Daniel and Dehm 2016; Lu et al. 2015), and over 20 splice variants have been identified in prostate cancer clinical samples and cell lines (Graham and Schweizer 2016; Robinson et al. 2015). Androgen receptor splice variant 7 (AR-V7) contains exons 1–3 and a C-terminal novel cryptic exon 3; as a result, the protein product lacks the hinge region and ligand-binding domain (Imamura and Sadar 2016; Luo 2016). AR-V7 lacks the ligand-binding domain and has been shown to be constitutively active in the absence of ligand, resulting in a potential mechanism of resistance to antiandrogen therapy (Chan et al. 2012; Hu et al. 2011). Whether all AR-Vs lacking the ligand-binding domain confer resistance to antiandrogens has been controversial, in part because not all of these variants contain the nuclear-localization signal (NLS), which allows the protein to cross the nucleus and perform its signaling function (Watson et al. 2015). Similarly, AR-V7 does not contain the NLS, but has been shown to be located in the nucleus (Chan et al. 2012; Hu et al. 2011). A recent study suggested that the presence of AR-V7 in tumor tissue is predictive of development of castration-resistant prostate cancer (CRPC) and indicates a poor prognosis of patients with CRPC (Qu et al. 2015).

a A large range has been reported relative to the frequency of expression for AR-V7 in prostate cancer; these discrepancies in reported frequencies may result from differences in treatment history, sample source, assay utilized, cut-off for positivity, and other factors (Antonarakis et al. 2014; Hörnberg et al. 2011; Qu et al. 2015; Robinson et al. 2015; Zhang et al. 2011).

b The increase in expression of the AR alternative splice variant AR-V7 in response to enzalutamide in preclinical models (Mostaghel et al. 2011; Hu et al. 2012) and the poor prognosis of enzalutamide-treated patients with detectable AR-V7 in circulating tumor cells are suggestive of a mechanism of resistance to this antiandrogen therapy (Antonarakis et al. 2014; Scher et al. 2016a). Additional studies have demonstrated that AR-V7 expression is associated with primary resistance to enzalutamide (Efstathiou et al. 2015).

c The increase in expression of the AR alternative splice variant AR-V7 in response to abiraterone in preclinical models (Mostaghel et al. 2011; Hu et al. 2012) and the poor prognosis of abiraterone-treated patients with detectable AR-V7 in circulating tumor cells is suggestive of a mechanism of resistance to this antiandrogen therapy (Antonarakis et al. 2014; Scher et al. 2016a).

d Preliminary reports suggest that the drug galeterone may be effective in patients with AR splice variants that lack the ligand-binding domain (Taplin et al. 2016a; Taplin et al. 2016b). EPI-506 (ESSA Pharma), an oral prodrug of EPI-002, is a drug reported as capable of targeting the AR N-terminal domainand has activity in several AR-V7–expressing cell lines and xenograft models (Andersen et al. 2010; Myung et al. 2013). Further, preclinical data suggests that the HSP90 inhibitor may effectively prevent alternative splicing of AR mRNA to the AR-V7 variant (Ferraldeschi et al. 2016). In other preclinical studies, niclosamide shows promise in combination therapies with enzalutamide or abiraterone in CRPC cells expressing AR-V7 by enhancing degradation of AR-V7 (Liu et al. 2014; Liu et al. 2016).

e Evidence also suggests that the success of docetaxel or cabazitaxel is not correlated with AR-V7 expression (Antonarakis et al. 2015; Scher et al. 2016a) suggesting that taxane therapy is a viable alternative in patients with AR-V7 positive circulating tumor cells. Recent studies suggest that nuclear-specific protein localization may enhance predictive value compared to nuclear-agnostic localization strategies (Scher et al. 2016b). Standards for timing and methods of AR-V7 detection for routine clinical use and therapy direction have not been established.

Contributors: Himisha Beltran, M.D.

Suggested Citation: Beltran, H. 2016. AR Splice Variant 7 (AR-V7) Expression in Prostate Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/prostate-cancer/ar/355/ (Updated December 21).

Last Updated: December 21, 2016

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