Related Experiment Video
Updated: Apr 5, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for
Daniel O'Neill1, Dominic Jones2, Mark Wade2
1AstraZeneca, Innovative Medicines, Discovery Sciences, Cambridge Science Park, Cambridge, CB4 0WG, UK.
Abstract:
The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated AR(W741L/C) mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of AR(W741L) highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, AR(W741L) transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients.
Insights
Androgen receptor (AR) mutations drive castrate-resistant prostate cancer (CRPC) by activating AR signaling. Targeting SGK1, a gene upregulated by AR mutants, shows promise for new CRPC therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor (AR) signaling persists in castrate-resistant prostate cancer (CRPC), necessitating novel therapeutic strategies.
- AR mutations can confer resistance to anti-androgen therapies by enabling agonist activity.
Purpose of the Study:
- To develop a physiologically relevant model for analyzing AR mutant functionality in advanced prostate cancer.
- To investigate the therapeutic potential of targeting specific AR mutant-driven pathways.
Main Methods:
- Development of a model system to study AR mutants, using the bicalutamide-activated AR(W741L/C) mutation as a proof of concept.
- Transcriptomic profiling of AR(W741L) to identify key upregulated genes.
- Evaluation of an SGK1 inhibitor to assess its effect on AR mutant activity.
Main Results:
- The AR(W741L) mutant demonstrated androgenic-like signaling and promoted growth in the presence of bicalutamide.
- Key upregulated genes identified included TIPARP, RASD1, and SGK1.
- SGK1 expression was high in a xenograft model and patient sample with the bicalutamide-activated AR mutant. Inhibition of SGK1 reduced AR(W741L) activity and growth promotion.
Conclusions:
- Exploiting functional differences between AR receptor isoforms offers a potential therapeutic avenue for CRPC.
- SGK1 inhibition represents a promising strategy to counteract AR mutant-driven signaling and growth in CRPC.
