Critical role of antioxidant programs in enzalutamide-resistant prostate cancer.
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Authors
Blatt, EB
Parra, K
Neeb, A
Buroni, L
Bogdan, D
Yuan, W
Gao, Y
Gilbreath, C
Paschalis, A
Carreira, S
DeBerardinis, RJ
Mani, RS
de Bono, JS
Raj, GV
Parra, K
Neeb, A
Buroni, L
Bogdan, D
Yuan, W
Gao, Y
Gilbreath, C
Paschalis, A
Carreira, S
DeBerardinis, RJ
Mani, RS
de Bono, JS
Raj, GV
Document Type
Journal Article
Date
2023-07-21
Date Accepted
2023-06-13
Abstract
Therapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand 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 dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive 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 of glutaminase enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was 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.
Citation
Oncogene, 2023, 42 (30), pp. 2347 - 2359
Source Title
Oncogene
Publisher
SPRINGERNATURE
ISSN
0950-9232
eISSN
1476-5594
Collections
Research Team
Cancer Biomarkers
Translational & Expt Med
PrCa Targeted Therapy
Translational & Expt Med
PrCa Targeted Therapy