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

Abstract

Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of such alterations on hormonal therapy.

Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

“…In contrast, enzalutamide did not reduce PDX-O growth, consistent with its parental biopsy being from a CRPC patient who had developed resistance to enzalutamide (Figure 6B and C). AR-V7 expression increases as PC patients progress to CRPC and develop treatment resistance (14,15,(22)(23)(24)(25)(26). Consistent with this, castration of CP50 PDX for 14 days significantly increased AR-V7 expression, with a less pronounced impact on AR-FL, C-MYC expression and AR signaling (Figure 6D Figure S13A and B).…”

“…Consistent with this, we demonstrate that the BET inhibitors, I-BET151 and JQ1, inhibit AR signaling and reduce AR-V7 expression in VCaP and LNCaP95 cells. Interestingly, both inhibitors had no effect on AR-V7 expression in 22Rv1 cells, probably due to its generation in this model, in part, resulting from AR genomic rearrangements, as opposed to alternative splicing (15,46,47). These data suggest that I-BET151 mediated AR-V7 regulation may be through the inhibition of alternative splicing, and indicate that patient selection for treatment with these agents should consider AR-V7 positive but AR genomic rearrangement negative tumors (30).…”

“…This has led to advances in antiandrogen therapy, with the successful development of abiraterone and enzalutamide (9)(10)(11)(12)(13). Despite these advances, primary resistance is common and secondary resistance on treatment inevitable in CRPC, in part due to expression of constitutively active AR splice variants that evade current antiandrogen treatment strategies (14,15,(21)(22)(23)(24)(25)(26). One promising strategy undergoing clinical evaluation in CRPC is targeting BET family proteins (ClinicalTrials.gov identifier: NCT02711956, NCT03150056).…”

“…However, primary and secondary resistance to both therapies is common and may, in part, be due to the expression of constitutively active AR splice variants of which AR variant 7 (AR-V7) is considered the most significant and best studied (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Consistent with this, recent studies have demonstrated that AR-V7 expression increases as patients progress to CRPC, and associates with resistance to current AR directed therapies (14,15,(22)(23)(24)(25)(26). AR-V7 lacks the AR ligand binding domain (LBD), but contains a cryptic exon 3 (derived from an intron) after AR exon 3 (27).…”

A prognostic model for stratifying clinical outcomes in chemotherapy-naive metastatic castration-resistant prostate cancer patients treated with abiraterone acetate

“…17,18 Recent evidence has revealed that structural variants of the AR gene are associated with the presence of AR splice variants, and may also be important drivers of treatment resistance. 19 In addition, AR gene aberrations (copy number change and/or mutations) in pre-treatment ctDNA have been linked to adverse outcomes in mCRPC patients commencing abiraterone and enzalutamide. 20,21 A biomarker panel incorporating CTC enumeration and LDH was also recently shown to predict OS in a post-hoc analysis of the COU-AA-301 trial.…”