In Vivo Characterization of Glutamine Metabolism Identifies Therapeutic Targets in Clear Cell Renal Cell Carcinoma

Authors

Akash K Kaushik
Amy Tarangelo
Lindsey K Boroughs
Mukundan Ragavan
Yuanyuan Zhang
Cheng-Yang Wu
Xiangyi Li
Kristen Ahumada
Jui-Chung Chiang
Vanina T Tcheuyap
Faeze Saatchi
Quyen N Do
Cissy Yong
Tracy Rosales
Christina Stevens
Aparna D Rao
Brandon Faubert
Panayotis Pachnis
Lauren G Zacharias
Hieu Vu
Feng Cai
Thomas P Mathews
Giannicola Genovese
Barbara S Slusher
Payal Kapur
Xiankai Sun
Matthew Merritt
James Brugarolas
Ralph J DeBerardinis

Publication Date

12-16-2022

Journal

Science Advances

Abstract

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.

Keywords

Humans, Mice, Animals, Carcinoma, Renal Cell, Glutaminase, Kidney Neoplasms, Glutamine, Isocitrate Dehydrogenase

Comments

Supplementary Materials

PMID: 36525494