Splicing of a Novel Androgen Receptor Exon Generates a Constitutively Active Androgen Receptor that Mediates Prostate Cancer Therapy Resistance
Open accessAbstract
The standard systemic treatment for prostate cancer (PCa) is androgen ablation, which causes tumor regression by inhibiting activity of the androgen receptor (AR). Invariably, PCa recurs with a fatal androgen-refractory phenotype. Importantly, the growth of androgen-refractory PCa remains dependent on the AR through various mechanisms of aberrant AR activation. Here, we studied the 22Rv1 PCa cell line, which was derived from a CWR22 xenograft that relapsed during androgen ablation. Three AR isoforms are expressed in 22Rv1 cells: a full-length version with duplicated exon 3 and two truncated versions lacking the COOH terminal domain (CTD). We found that CTD-truncated AR isoforms are encoded by mRNAs that have a novel exon 2b at their 3′ end. Functionally, these AR isoforms are constitutively active and promote the expression of endogenous AR-dependent genes, as well as the proliferation of 22Rv1 cells in a ligand-independent manner. AR mRNAs containing exon 2b and their protein products are expressed in commonly studied PCa cell lines. Moreover, exon 2b–derived species are enriched in xenograft-based models of therapy-resistant PCa. Together, our data describe a simple and effective mechanism by which PCa cells can synthesize a constitutively active AR and thus circumvent androgen ablation. [Cancer Res 2008;68(13):5469–77]
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Tumor alterations that reactivate AR signaling during treatment with an ARSI have been identified.
“We and other groups have identified tumor alterations that reactivate AR signaling during treatment with an ARSI2,22–29.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [28]
The Abstract and Discussion (pages unavailable) identify a novel AR splice variant that is constitutively active and enriched in therapy-resistant prostate cancer xenografts. The paper links this alteration to resistance to androgen ablation, but does not establish that it arose during treatment with a specific AR signaling inhibitor (ARSI). (LLM, conf=0.82)
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“These mechanisms of resistance include AR gene amplification 22,23 , AR enhancer amplification 2,24,25 , AR mutation 26 , AR genomic structural rearrangements 27 , AR splice variants 28 and polymorphisms in androgen metabolism genes 29 .”
- Authors
- Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L., & Tindall, D. J.
- Affiliations
- Mayo Clinic (US)
- University of Washington (US)
- Venue
- Cancer Research
- Published
- 2008-07-01
- Volume
- 68
- Issue
- 13
- Pages
- 5469-5477
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2663383
- OpenAlex
- W2085847636
- Cited by
- 834
- References
- 33
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 41 · 2023: 39 · 2022: 41 · 2021: 44 · 2020: 49 · 2019: 44 · 2018: 47 · 2017: 52 · 2016: 77 · 2015: 71 · 2014: 57 · 2013: 77 · 2012: 55
- FWCI
- 32.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA121277, CA 91956, CA121277, P50CA091956)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065236, DK065236)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- androgen receptor, alternative splicing, prostate cancer, androgen-refractory prostate cancer, androgen ablation resistance, 22Rv1 cells, ligand-independent receptor activation, xenograft models
- MeSH terms
- Animals, Base Sequence, Exons, Humans, Male, Mice, Inbred BALB C, Molecular Sequence Data, Prostatic Neoplasms, Receptors, Androgen, Transfection, Transplantation, Heterologous, Gene Expression Regulation, Neoplastic, Mice, SCID, Alternative Splicing, Antineoplastic Agents, Hormonal, Drug Resistance, Neoplasm, Protein Isoforms, Cell Line, Tumor, Cell Proliferation, Mice
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