Antioxidant Programs Are Essential for Enzalutamide-Resistant Prostate Cancer

Therapy resistance to second generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). In order to identify which patients will develop therapy resistance and the underlying cause, it is critical to characterize detailed mechanisms of resistance to improve patient outcomes. To identify the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted that enzalutamide-resistant PCa cells and castration-resistant PCa (CRPC) tumors had dramatically higher levels of both basal and inducible levels of reactive oxygen species (ROS) than either enzalutamide-sensitive PCa cells or primary therapy-naïve tumors, respectively. Unbiased metabolomic evaluation identified that glutamine metabolism was consistently upregulated in enzalutamide-resistant PCa cells and CRPC tumors. Stable isotope tracing studies suggest that this enhanced glutamine metabolism drives an antioxidant program that allows these cells to tolerate higher basal levels of ROS. Inhibition of glutamine metabolism with either a small-molecule glutaminase inhibitor or genetic knockout blocked this antioxidant pathway, further enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of the compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was further validated by targeting another antioxidant program driver, ferredoxin 1. Taken together, our data identify a metabolic need to maintain antioxidant programs and a potentially targetable metabolic vulnerability in enzalutamide-resistant PCa.

Author dc:creator

• Blatt, Eliot Benjamin

Contributors dc:contributor

• Kittler, Ralf
• DeBerardinis, Ralph J.
• Minna, John D.
• Raj, Ganesh V.

• Nitriles
• Prostatic Neoplasms, Castration-Resistant
• Drug Resistance, Neoplasm

Language dc:language

en

Identifier

1522122338

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10585