Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents:...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Second-generation androgen receptor axis-targeted (ARAT) agents, including abiraterone and enzalutamide, offer improved survival for castration-resistant prostate cancer (CRPC) patients by enhancing androgen receptor (AR) blockade.
• Despite advancements, resistance to ARAT agents is common, with mechanisms including complete AR independence or indifference, and persistent AR dependency.
• AR-independent mechanisms, such as ligand-independent AR activation via splice variants or bypass pathways involving the glucocorticoid receptor, render current ARAT agents ineffective.

Purpose of the Study:

• To review recent advancements in understanding AR-independent resistance mechanisms in CRPC.
• To explore strategies for developing next-generation AR axis blockade therapies.
• To identify approaches to overcome refractory mechanisms in advanced prostate cancer.

Main Methods:

• Literature review of recent studies on AR signaling, resistance mechanisms, and novel therapeutic strategies in CRPC.
• Analysis of AR splice variants, nonsense mutations, post-translational modifications, and bypass pathways.
• Evaluation of emerging AR axis-targeted agents and combination therapies.

Main Results:

• Identified distinct AR-dependent and AR-independent resistance pathways in CRPC.
• Highlighted the role of AR splice variants (e.g., AR-V7) and glucocorticoid receptor in AR-independent progression.
• Demonstrated that ARAT agents are ineffective against AR-independent CRPC.

Conclusions:

• Overcoming AR-independent mechanisms is crucial for improving treatment outcomes in CRPC.
• Next-generation ARAT agents and novel therapeutic strategies are needed to address resistance.
• Targeting bypass pathways and understanding AR modifications are key to future CRPC therapy.