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
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).
Suggested Citation: Beltran, H. 2016. AR (AR) in Prostate Cancer. My Cancer
(Updated September 12).
Last Updated: September 12, 2016
AR c.2632A>G (T878A) Mutation in Prostate Cancer
|Location of mutation
||Ligand-binding domain (exon 8)
|Frequency of AR mutations in
castration-resistant prostate cancer
et al. 2012; Robinson
et al. 2015; Taylor
et al. 2010)
|Frequency of T878A mutation among AR-mutated
castration-resistant prostate cancers
||19–33% (COSMIC; Robinson et al.
|Implications for Targeted Therapeutics
|Response to hydroxyflutamide
||Unknown at this timea
|Response to bicalutamide
||Unknown at this timeb
|Response to enzalutamide
||Unknown at this timec
|Response to abiraterone
||Unknown at this timed
|Response to novel targeted therapies
||Unknown at this timee
|Response to other therapies
||Unknown at this time
The AR T878A mutation occurs in the ligand
binding domain of the androgen receptor and
alters the steroid binding properties of the mutated receptor
(Veldscholte et al.
1990). The mutated receptor also experiences activation by progesterones (Fenton et al. 1997;
Taplin et al. 1995; Taplin et al.
1999), and, in the setting of double mutant also harboring L702H, experiences activation
by hydrocortisones (Zhao
et al. 2000), which may offer one explanation for resistance to antiandrogen therapies.
a Previous in vitro reports agree that AR harboring the T878A mutation is activated, rather than inhibited, by
hydroxyflutamide Fenton et
al. 1997; Taplin et
al. 1995; Taplin
et al. 1999). Recent preclinical data suggest that hydroxyflutamide exhibits partial
agonist effects on the AR T878A (Lallous et al. 2016).
b Some reports suggest the T878A-mutated AR may be sensitive to treatment
with dutasteride and bicalutamide (Chen et al. 201; Taplin et al.
1999) although recent preclinical data demonstrate that bicalutamide possesses agonist
activity toward AR T878A (Lallous
et al. 2016).
c This mutation persists in
the setting of enzalutamide therapy, suggesting continued fitness of cells containing this mutation (Wyatt et al. 2016).
However, some case reports suggest that patients harboring AR T878A may still be responsive to
et al. 2015), although recent preclinical data suggest that enzalutamide may exhibit
partial agonist effects on the AR T878A (Lallous et al. 2016).
d The emergence of AR T878A has been detected in patients in the setting of
abiraterone treatment and is associated with poor outcomes, suggesting that this mutation may confer resistance to this
therapy (Azad et al.
2015; Chen et al.
2015; Romanel et
al. 2015; Wyatt et
e Preclinical reports suggest that galeterone may be particularly effective
against cancer cells expressing T878A-mutated AR by enhancing degradation of the mutated receptor (Yu et al. 2014).The
novel therapeutic CH5137291 appears to be an effective therapy for targeting cells with this
mutation in early preclinical studies (Ishikura et al. 2015).
Suggested Citation: Beltran, H. 2016. AR c.2632A>G (T878A) Mutation in Prostate Cancer. My Cancer
(Updated December 21).
Last Updated: December 21, 2016
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