Androgen receptor splice variant 7 expression levels distinguish AR-mutated from nonmutated metastatic castration-resistant prostate cancers
Alec Paschalis, Ines Figueiredo, Denisa Bogdan, Arian Lundberg, Rita Santos, Bora Gurel, Tarek Taha, Ossian Longoria, Ana Ferreira, Claudia Bertan, Nicholas Brittain, Ryan Nelson, Laura Walker, Antje Neeb, Jonathan Welti, Wei Yuan, Costas Mitsopoulos, Stephen R. Plymate, Michael C. Haffner, Adam G. Sowalsky, Suzanne Carreira, Adam Sharp, Luke Gaughan, Johann de Bono
Alec Paschalis, Ines Figueiredo, Denisa Bogdan, Arian Lundberg, Rita Santos, Bora Gurel, Tarek Taha, Ossian Longoria, Ana Ferreira, Claudia Bertan, Nicholas Brittain, Ryan Nelson, Laura Walker, Antje Neeb, Jonathan Welti, Wei Yuan, Costas Mitsopoulos, Stephen R. Plymate, Michael C. Haffner, Adam G. Sowalsky, Suzanne Carreira, Adam Sharp, Luke Gaughan, Johann de Bono
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Research Article Clinical Research Oncology

Androgen receptor splice variant 7 expression levels distinguish AR-mutated from nonmutated metastatic castration-resistant prostate cancers

Abstract

New androgen receptor (AR) pathway inhibitors (ARPIs) in clinical development, including AR degraders and CYP11A inhibitors, largely target ligand-dependent AR activation and have reported antitumor activity in metastatic castration-resistant prostate cancer (mCRPC) resistant to established ARPIs, predominately against tumors with AR mutations. We hypothesized that AR-mutated mCRPC exhibits lower AR splice variant 7 (AR-V7) expression and remains full-length–AR (FL-AR) driven, explaining, in part, the antitumor activity of these AR ligand–binding domain (LBD) targeting drugs. The data herein demonstrate that mCRPC tissue biopsies with detectable AR mutations express significantly lower levels of AR-V7 protein and associate with better overall survival and enhanced sensitivity to ARPIs. This is independent of differences in the total number of global splicing events but may be related to differences in splicing factor expression between AR-mutated and nonmutated mCRPC. In conclusion, AR-mutated mCRPC frequently exhibits low AR-V7 expression, arguably explaining the enhanced sensitivity to ARPIs observed in these cancers. Consequently, AR mutation status may serve as a biomarker to predict response to AR-directed therapies.

Authors

Alec Paschalis, Ines Figueiredo, Denisa Bogdan, Arian Lundberg, Rita Santos, Bora Gurel, Tarek Taha, Ossian Longoria, Ana Ferreira, Claudia Bertan, Nicholas Brittain, Ryan Nelson, Laura Walker, Antje Neeb, Jonathan Welti, Wei Yuan, Costas Mitsopoulos, Stephen R. Plymate, Michael C. Haffner, Adam G. Sowalsky, Suzanne Carreira, Adam Sharp, Luke Gaughan, Johann de Bono

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Figure 1

AR mutation is associated with a better clinical outcome in advanced PC.

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AR mutation is associated with a better clinical outcome in advanced PC...
(A) Oncoprint diagram illustrating the frequency and type of AR alteration in a cohort of 475 metastatic CRPC (mCRPC) biopsies with available next-generation sequencing (NGS) data (RMH clinical cohort). (B–F) Kaplan-Meier curves comparing clinical outcomes between patients with and without detectable AR mutation (RMH clinical cohort). Detectable AR mutation in mCRPC tissue biopsy associated with improved overall survival from prostate cancer (PC) diagnosis (B; n = 122, P < 0.05; Log-rank test) and development of CRPC (C; n = 122, P < 0.005; Log-rank test), with a longer time to development of CRPC (D; n = 122, P > 0.05; Log-rank test). Detectable AR mutation also associated with a longer time on first AR pathway inhibitor (ARPI) (E; n = 112, P < 0.0001; Log-rank test) and overall survival from initiation of first ARPI (F; n = 112, P < 0.0001; Log-rank test). (G) Waterfall plot demonstrating percentage (%) PSA change from baseline 12 weeks after commencement of first ARPI (Abiraterone/Enzalutamide). All patients received ARPI in the CRPC setting. Each bar represents an individual patient within the RMH clinical cohort with sufficient clinical data for evaluation. Patients with a detectable AR mutation shown in green. Those without a detectable AR mutation shown in grey. (H) Lollipop graph illustrating the location and frequency of AR mutation identified within the evaluated RMH clinical cohort of mCRPC patient biopsies, with the most frequent mutations highlighted in red. (I–K) Kaplan-Meier curves comparing clinical outcomes between patients with AR LBD mutations, AR non-LBD mutations, or without detectable AR mutation (RMH clinical cohort). Overall, AR LBD mutation associated with significantly improved overall survival from diagnosis (I; n = 122, P = 0.005; Log-rank test), overall survival from development of CRPC (J; n = 122, P < 0.005; Log-rank test), and time on first ARPI (K; n = 112, P = 0.0001; Log-rank test), than those without detectable AR mutations. However, this was not the case for patients with non-LBD AR mutations. NTD, AR n-terminal domain; ZFD, AR zinc-finger domain; LBD, AR ligand binding domain.