Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer
Daisuke Obinata1,2, Mitchell G Lawrence2,3,4, Kenichi Takayama5
1Department of Urology, Nihon University School of Medicine, Tokyo, Japan.
Abstract:
The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.
Insights
Advanced prostate cancer treatments targeting the androgen receptor (AR) eventually fail due to resistance. Understanding AR signaling and collaborative transcription factors (TFs) is key to developing new therapies using patient-derived models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The androgen receptor (AR) is a primary target in advanced prostate cancer.
- Resistance to AR-directed therapies is inevitable, driven by AR reactivation and dysregulated cofactors/transcription factors (TFs).
Purpose of the Study:
- To review mechanisms of AR-directed therapy resistance in prostate cancer.
- To explore the interplay between AR and collaborative TFs.
- To highlight the utility of patient-derived models for novel drug discovery.
Main Methods:
- Literature review of AR signaling pathways and resistance mechanisms.
- Analysis of the intersection between AR and collaborative TFs.
- Discussion of preclinical models, including xenografts and organoids.
Main Results:
- Resistance mechanisms involve AR reactivation and altered AR cofactor/TF interactions.
- Targeting BET proteins or OCT1 presents potential therapeutic strategies.
- Patient-derived models are crucial for testing novel therapeutic approaches.
Conclusions:
- Elucidating AR and collaborative TF interactions is vital for overcoming treatment resistance.
- Patient-derived models offer promising platforms for preclinical drug screening and development.
- Novel therapeutic strategies targeting AR or its collaborators are needed for advanced prostate cancer.
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