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 3

AR amplification and AR-V7 expression in AR-mutated mCRPC clinical biopsies.

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AR amplification and AR-V7 expression in AR-mutated mCRPC clinical biop...
(A) Oncoprint diagram illustrating the incidence of AR gene amplification among evaluated patients with and without detectable AR mutations (RMH clinical cohort). (B) Bar chart of AR copy number in mCRPC patient biopsies with and without detectable AR mutations (RMH clinical cohort). Threshold for classification as AR gene amplification indicated by dashed grey line. (C) Bar chart of nuclear (Nuc) and cytoplasmic (Cyto) AR-n terminal domain (NTD) protein levels (IHC H-Score) in mCRPC patient biopsies with and without detectable AR mutations (RMH clinical cohort). (D) Bar chart of nuclear AR-V7 protein levels (IHC H-Score) in mCRPC patient biopsies with and without detectable AR mutations, subdivided into those with and without AR amplification. Median H-Score and interquartile range shown. (E and F) Oncoprint diagram illustrating the top cooccurring genetic alterations other than AR amplification found on targeted sequencing of mCRPC tissue biopsies with and without detectable AR mutation. Statistical significance in B and C determined by Mann-Whitney test. Statistical significance in D determined by Kruskal-Wallis test. (*P < 0.05, **P < 0.01, ***P < 0.001). Nuc, Nuclear IHC staining; Cyto, Cytoplasmic IHC staining.