Why?

 For patients with advanced prostate cancer, androgen receptor signaling inhibitors, such as enzalutamide, have shown utility in improving survival [1, 2]. However, therapy resistance and disease progression is common, with ~30,000 deaths from prostate cancer each year in the U.S. alone [3]. We sought to decipher metabolic drivers involved in enzalutamide-resistant prostate cancer (EnzR-PCa).

 Main Findings

 Herein, we identified that enzalutamide induces oxidative stress by blocking androgen receptor-regulated glutamine and antioxidant metabolism genes. Enzalutamide-resistant prostate cancers are characterized by higher basal and inducible levels of reactive oxygen species. Using comparative unbiased metabolomics in paired enzalutamide-sensitive (EnzS) and EnzR-PCa cell lines, we noted that antioxidant pathways driven by glutamine metabolism were dramatically enhanced in EnzR-PCa cell lines. We postulated that the enhanced antioxidant pathways enable these enzalutamide-resistant prostate cancers to tolerate higher levels of oxidative stress, and that this dependency represents a targetable vulnerability. In support, we demonstrated a greater sensitivity of enzalutamide-resistant prostate cancers to agents that increase oxidative stress or block antioxidant pathways. We have specifically shown that either small-molecule inhibitors or genetic ablation of key enzymes involved in either glutamine or ferredoxin metabolism significantly slow the growth of enzalutamide-resistant prostate cancers.

Significance

 This is the first study to comprehensively characterize the comparative metabolism of enzalutamide-sensitive and enzalutamide-resistant prostate cancers in cell lines in vitro, xenografts in vivo, patient-derived organoids, and patient tumors. From our studies, we have identified that antioxidant pathways in enzalutamide-resistant prostate cancers represent a targetable metabolic vulnerability. Our studies demonstrate that targeted disruption of either glutamine or ferredoxin metabolism block the critical antioxidant programs needed for the survival of enzalutamide-resistant prostate cancers and may translate into an effective clinical strategy.

 References:

1. Hussain, M., et al., Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med, 2018. 378(26): p. 2465-2474.
2. Komura, K., et al., Comparison of Radiographic Progression-Free Survival and PSA Response on Sequential Treatment Using Abiraterone and Enzalutamide for Newly Diagnosed Castration-Resistant Prostate Cancer: A Propensity Score Matched Analysis from Multicenter Cohort. J Clin Med, 2019. 8(8).
3. Siegel, R.L., et al., Cancer statistics, 2023. CA Cancer J Clin, 2023. 73(1): p. 17-48.