Androgen receptor splice variant 7 expression levels distinguish AR-mutated from nonmutated metastatic castration-resistant prostate cancers
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
- Nicholas Brittain
- Jonathan Welti (ORCID: https://orcid.org/0000-0002-9433-8138)
- Ossian Longoria (ORCID: https://orcid.org/0000-0002-0203-3987)
- Bora Gürel (ORCID: https://orcid.org/0000-0002-5018-8078)
- Antje Neeb (ORCID: https://orcid.org/0000-0002-6516-2938)
- Arian Lundberg (ORCID: https://orcid.org/0000-0002-6630-2787)
- Adam G. Sowalsky (ORCID: https://orcid.org/0000-0003-2760-1853)
- Denisa Bogdan (ORCID: https://orcid.org/0000-0002-3017-4832)
- Luke Gaughan
- Costas Mitsopoulos (ORCID: https://orcid.org/0000-0002-9116-5921)
- Laura Walker (ORCID: https://orcid.org/0000-0002-5298-924X)
- Stephen R. Plymate (ORCID: https://orcid.org/0000-0002-7597-6943)
- Suzanne Carreira (ORCID: https://orcid.org/0000-0002-5077-5379)
- Wei Yuan (ORCID: https://orcid.org/0000-0002-1122-6481)
- Alec Paschalis (ORCID: https://orcid.org/0000-0001-9566-5096)
- Ines Figueiredo
- Johann de Bono
- Claudia Bertan
- Michael C. Haffner
- Ana Ferreira
- Rita Santos
Institutions
- Institute of Cancer Research (GB)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Royal Marsden Hospital (GB)
- National Cancer Institute (US)
- Newcastle University (GB)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1172/jci198193
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research