Exploiting AR-Synergistic Metabolic Vulnerabilities in Prostate Cancer

Resistance to androgen deprivation therapy remains a major clinical challenge in prostate cancer, necessitating alternative therapeutic strategies. The androgen receptor (AR) plays a central role in driving resistance through mechanisms including enhanced AR signaling, DNA repair, and autophagy. In this issue of Cancer Research, Cordova and colleagues identify a metabolic vulnerability in AR protein synthesis, showing that alternate-day fasting (ADF) impairs AR translation by inducing ribosome collisions on AR mRNA. This stress response activates kinases such as p38 MAPK and selectively reduces AR protein levels, independent of transcription or protein stability. Notably, ADF enhances the efficacy of enzalutamide across multiple prostate cancer models. Unlike conventional AR-targeting approaches, ADF reveals a posttranscriptional dependency of AR expression under nutrient stress while sparing most other proteins. These findings highlight a novel translational vulnerability in prostate cancer and support combining dietary interventions with AR-targeted therapies to overcome resistance and improve patient outcomes. See related article by Cordova et al., p. 4182.