Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The androgen receptor (AR) signaling pathway is crucial in prostate cancer development and progression.
• Castration-resistant prostate cancer (CRPC) emerges after androgen deprivation therapy (ADT) failure, often due to persistent AR activity.
• Current therapies targeting AR, like enzalutamide and abiraterone, can be overcome by AR pathway alterations.

Purpose of the Study:

• To provide a comprehensive review of AR signaling alterations driving CRPC.
• To detail the mechanisms of resistance, including increased AR expression, AR mutations, and AR variants.
• To explore novel therapeutic strategies targeting AR resistance mechanisms.

Main Methods:

• Literature review and synthesis of current research on AR signaling in prostate cancer.
• Analysis of the roles of AR expression, mutations, and variants in CRPC.
• Examination of emerging therapeutic strategies distinct from current ligand-centric approaches.

Main Results:

• Direct alterations in the AR signaling axis are common mechanisms for CRPC development and progression.
• Increased AR expression, AR gain-of-function mutations, and AR variants contribute to therapy resistance.
• Alterations in AR coregulators also play a significant role in CRPC.
• Emerging therapies aim to inhibit these resistance mechanisms through novel approaches.

Conclusions:

• The androgen receptor (AR) signaling axis is central to all stages of prostate cancer, including CRPC.
• Understanding AR alterations is critical for overcoming treatment resistance.
• Novel therapeutic strategies targeting AR pathway modifications offer promise for future CRPC treatment.