Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy

Abstract

Upregulation of constitutively-active androgen receptor splice variants (AR-Vs) has been implicated in AR-driven tumor progression in castration-resistant prostate cancer. To date, functional studies of AR-Vs have been focused mainly on their ability to regulate gene expression independent of the full-length AR (AR-FL). Here, we showed that AR-V7 and ARv567es, two major AR-Vs, both facilitated AR-FL nuclear localization in the absence of androgen and mitigated the ability of the antiandrogen enzalutamide to inhibit AR-FL nuclear trafficking. AR-V bound to the promoter of its specific target without AR-FL, but co-occupied the promoter of canonical AR target with AR-FL in a mutually-dependent manner. AR-V expression attenuated both androgen and enzalutamide modulation of AR-FL activity/cell growth, and mitigated the in vivo antitumor efficacy of enzalutamide. Furthermore, ARv567es levels were upregulated in xenograft tumors that had acquired enzalutamide resistance. Collectively, this study highlights a dual function of AR-Vs in mediating castration resistance. In addition to trans-activating target genes independent of AR-FL, AR-Vs can serve as a “rheostat” to control the degree of response of AR-FL to androgen-directed therapy via activating AR-FL in an androgen-independent manner. The findings shed new insights into the mechanisms of AR-V-mediated castration resistance and have significant therapeutic implications.

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…A key question in the field has been whether AR-Vs regulate a classical AR-driven transcriptional program or whether they have distinct gene targets, with evidence for both concepts being reported (Guo et al 2009, Hu et al 2009, Chan et al 2012, Tsai et al 2012, Cao et al 2014. Recently, work from Dehm's group has provided a possible explanation for these discrepant findings by identifying proliferative vs anti-proliferative AR gene signatures mediated by differences in DHT dose or AR expression, with the former mitotic gene signature resembling that driven by AR-Vs (Li et al 2013).…”

“…The finding that AR-Vs can heterodimerize with AR-FL or with other AR-Vs , Cao et al 2014, Xu et al 2015 raises the possibility that the nature and relative expression of different AR-Vs and AR-FL in single cells could influence distinct transcriptional outputs.…”

Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: Biomarker for treatment selection exclusion or inclusion?

“…Other investigators have suggested that targeting both AR-V7 and the AR ligand-binding domain may be useful in early therapies. 10,11 AR-V7 appears to be induced after ADT, potentially selecting for circulating tumor cells which exhibit this splice variant. 11 A recent study by Cao et al found that AR-Vs can cause AR-FL to induce gene expression in the absence of androgen, in addition to AR-V ability to be active in the absence of androgen on their own.…”

“…11 A recent study by Cao et al found that AR-Vs can cause AR-FL to induce gene expression in the absence of androgen, in addition to AR-V ability to be active in the absence of androgen on their own. 10 Targeting both AR-V7 and the AR-ligand binding domain may help prevent resistance mechanisms from emerging.…”

“…5,10,18,19 AR splice variants lacking the ligand-binding domain would likely exhibit similar effects with drug efficacy as AR-V7. Future research should determine the prevalence of similar AR splice variants in CRPC patients, whether they also correlate with decreased AR-directed therapy efficacy, and if an assay can reliably detect these splice variants in patients.…”