Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities
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By
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Juntao Guo
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Ke Wu
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Zheng Ma
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Shuai Guo
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Fei Wang
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Lingxiang Lu
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May 21, 2026
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Clinical Scorecard: Reactivation of Androgen Receptors in Castration-Resistant Prostate Cancer: Mechanisms, Epigenetic Changes, and Treatment Vulnerabilities
At a Glance
| Category | Detail |
|---|
| Condition | |
| Key Mechanisms | AR amplification, overexpression, ligand-binding domain mutations, splice variants, intratumoral androgen synthesis, bypass signaling, altered AR co-regulators, epigenetic changes. |
| Target Population | |
| Care Setting | |
Key Highlights
- CRPC is characterized by persistent AR signaling despite androgen deprivation.
- AR reactivation involves multiple overlapping mechanisms that promote treatment resistance.
- Epigenetic changes play a crucial role in maintaining AR-dependent transcription.
- Therapeutic strategies include AR degraders, PARP inhibitors, epigenetic therapies targeting EZH2, BET proteins, p300/CBP, LSD1, or HDACs.
- Biomarker-guided treatment may enhance therapy selection for CRPC patients.
Guideline-Based Recommendations
Diagnosis
- Assess AR signaling status and resistance mechanisms in CRPC.
Management
- Utilize next-generation AR pathway inhibitors, consider combination therapies, and include epigenetic therapies.
Monitoring & Follow-up
- Regularly evaluate treatment response, resistance markers, and changes in AR signaling pathways.
Risks
- Monitor for potential side effects of AR-targeted therapies and resistance development.
Patient & Prescribing Data
Patients with advanced prostate cancer who have progressed on standard therapies.
Consider AR-targeted therapies based on individual resistance mechanisms and biomarker profiles.
Clinical Best Practices
- Incorporate genetic and epigenetic profiling in treatment planning.
- Monitor for changes in AR signaling pathways during therapy.
- Consider combination therapies targeting multiple resistance mechanisms.
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