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Updated: Mar 25, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Aryl hydrocarbon receptor is critical for both AR-dependent and AR-indifferent enzalutamide resistance in
Chia-Hui Chen1, Ryan Brown2, Donald J Vander Griend2
1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
Abstract:
The introduction of next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide (ENZ), has improved the clinical management of castration-resistant prostate cancer (CRPC). However, acquired resistance to these therapies often develops rapidly, and the underlying resistance mechanisms remain largely unclear. Here, we identified the aryl hydrocarbon receptor (AHR) as a crucial operator of ENZ-resistant CRPC. AHR is upregulated in three ENZ-resistant human CRPC cell lines (C4-2BENZR, CWR-R1ENZR, and VCaPENZR) as well as in high-grade prostate tumors from patients receiving ENZ treatment. Stable knockdown of AHR substantially reduced the growth of ENZ-resistant CRPC cells and xenografts. Mechanistically, AHR engages in distinct transcriptional programs in a cellular context-dependent manner. AHR directly regulates the transcription and expression of androgen receptor (AR)/glucocorticoid receptor (GR) co-target genes in CWR-R1ENZR cells, suggesting an AR-dependent mechanism of ENZ resistance. AHR promotes neuroendocrine differentiation while suppressing the expression of AR/GR targets in C4-2BENZR cells, indicating an AR-indifferent mechanism of ENZ resistance. The diverse mechanisms triggered by ENZ were also manifested in clinical samples. Collectively, these findings characterize AHR's contribution to ENZ resistance in CRPC and illuminate the potential of targeting AHR for treating ARSI-resistant advanced prostate cancer.
Insights
Aryl hydrocarbon receptor (AHR) drives resistance to enzalutamide (ENZ) in castration-resistant prostate cancer (CRPC). Targeting AHR offers a potential strategy to overcome therapy resistance in advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide (ENZ) have advanced castration-resistant prostate cancer (CRPC) treatment.
- Acquired resistance to ARSIs is a significant clinical challenge, with underlying mechanisms often unclear.
Purpose of the Study:
- To identify key molecular drivers of enzalutamide resistance in castration-resistant prostate cancer.
- To elucidate the mechanisms by which these drivers confer resistance.
- To explore potential therapeutic targets for overcoming ARSI resistance.
Main Methods:
- Upregulation of aryl hydrocarbon receptor (AHR) was assessed in ENZ-resistant CRPC cell lines and patient tumors.
- AHR's role in ENZ-resistant CRPC growth was evaluated using stable knockdown models in vitro and in vivo.
- Mechanistic studies investigated AHR's transcriptional regulation of androgen receptor (AR)/glucocorticoid receptor (GR) co-target genes and its impact on cellular differentiation.
Main Results:
- Aryl hydrocarbon receptor (AHR) was found to be upregulated in ENZ-resistant CRPC cell lines and patient tumors.
- Stable knockdown of AHR significantly inhibited the growth of ENZ-resistant CRPC cells and xenografts.
- AHR mediated resistance through distinct mechanisms: AR-dependent regulation of AR/GR co-target genes in one cell line and AR-independent promotion of neuroendocrine differentiation in another.
Conclusions:
- Aryl hydrocarbon receptor (AHR) is a critical mediator of enzalutamide resistance in castration-resistant prostate cancer.
- AHR confers resistance via context-dependent transcriptional programs, impacting AR signaling and cellular differentiation.
- Targeting AHR presents a promising therapeutic strategy for patients with advanced prostate cancer who develop resistance to ARSI therapies.
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