These relapses are generally associated with increases in serum prostate-specific antigen (PSA), suggesting that androgen receptor (AR) activity has again been restored. Synthesis of these precursor steroids is dependent on the enzyme CYP17A1, and a specific inhibitor of this enzyme (abiraterone) was recently approved for treatment of CRPC, but most men who initially respond will relapse within 1 to 2 years ( 6–9). One mechanism driving these resistant tumors is intratumoral synthesis of androgens (testosterone and dihydrotestosterone, DHT) from precursor steroids produced by the adrenal glands or de novo from cholesterol ( 1–6). Introductionīlockade of testicular androgen production by surgical or medical castration (androgen deprivation therapy) is a standard treatment for metastatic prostate cancer, but tumors invariably relapse and progress into a stage termed castration-resistant prostate cancer (CRPC). These results indicate that agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR LBD before the emergence of additional resistance mechanisms. Moreover, we find that increases in the major AR splice variant (AR-V7) occur rapidly through a feedback mechanism and can mediate low-basal AR activity immediately after androgen deprivation, but cannot mediate the high-level AR activity in relapsed tumors. We show that AR reactivation in abiraterone-resistant VCaP xenografts is not associated with restoration of intratumoral androgens. Previous studies have indicated that restoration of androgen receptor (AR) transcriptional activity in prostate cancer that relapses after castration (castration-resistant prostate cancer) or after subsequent therapy with abiraterone, a CYP17A1 inhibitor that further suppresses androgen synthesis, may be mediated by abiraterone-resistant intratumoral androgen synthesis or by constitutively active AR splice variants lacking the ligand-binding domain (LBD). Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand-binding domain. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA.Ĭonclusions: AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR.
However, despite the increases in AR-V7 mRNA, it remained a minor transcript (<1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. This shift toward AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. In contrast, mRNA encoding full-length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared with xenografts before castration, with an increase in AR-V7 relative to AR-FL. Results: AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR coregulators.
Purpose: Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer that progresses after castration (castration-resistant prostate cancer CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear.Įxperimental Design: Prostate cancer xenografts were examined to identify mechanism of progression after castration and abiraterone.