Targeting Metabolic Vulnerabilities to Overcome Prostate Cancer Resistance: Dual Therapy with Apalutamide and Complex...

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Research

Background:

• Prostate cancer (PCa) frequently develops resistance to androgen deprivation therapy (ADT).
• Understanding the metabolic adaptations driving PCa progression and treatment resistance is crucial for developing novel therapies.
• Distinct metabolic dependencies exist across different PCa subtypes.

Purpose of the Study:

• To investigate the metabolic profiles of various PCa subtypes.
• To explore the synergistic effects of combining androgen receptor (AR) inhibition with mitochondrial complex I inhibition (IACS).
• To identify potential therapeutic strategies targeting metabolic vulnerabilities in drug-resistant PCa.

Main Methods:

• Examined metabolic behaviors of normal prostate epithelial cells (PNT1A) and PCa cell lines (LNCaP, C4-2, PC-3) under different treatments.
• Utilized cellular bioenergetics analysis to assess mitochondrial activity and glycolysis.
• Investigated the impact of galactose supplementation and glucose deprivation on PCa cell sensitivity.

Main Results:

• Androgen-dependent PCa cells showed heightened oxidative phosphorylation (OXPHOS).
• The combination of AR inhibition and IACS significantly inhibited proliferation in multiple PCa cell lines.
• IACS reduced OXPHOS, while AR inhibition affected glycolysis; glucose deprivation enhanced sensitivity to mitochondrial inhibition.

Conclusions:

• AR signaling and metabolic reprogramming are intricately linked to PCa treatment resistance.
• Targeting PCa subtype-specific metabolic vulnerabilities, particularly mitochondrial function and glycolysis, presents a promising therapeutic avenue.
• Combining AR inhibition with mitochondrial complex I inhibition offers a potential strategy against drug-resistant prostate cancer.