In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

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 -mutant clear cell RCC (ccRCC) retained metabolic features of hum...

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Published in:Science advances 2022-12, Vol.8 (50), p.eabp8293
Main Authors: Kaushik, Akash K, Tarangelo, Amy, Boroughs, Lindsey K, Ragavan, Mukundan, Zhang, Yuanyuan, Wu, Cheng-Yang, Li, Xiangyi, Ahumada, Kristen, Chiang, Jui-Chung, Tcheuyap, Vanina T, Saatchi, Faeze, Do, Quyen N, Yong, Cissy, Rosales, Tracy, Stevens, Christina, Rao, Aparna D, Faubert, Brandon, Pachnis, Panayotis, Zacharias, Lauren G, Vu, Hieu, Cai, Feng, Mathews, Thomas P, Genovese, Giannicola, Slusher, Barbara S, Kapur, Payal, Sun, Xiankai, Merritt, Matthew, Brugarolas, James, DeBerardinis, Ralph J
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Cancer
Carcinoma, Renal Cell - drug therapy
Carcinoma, Renal Cell - metabolism
Glutaminase - therapeutic use
Glutamine - metabolism
Humans
Isocitrate Dehydrogenase
Kidney Neoplasms - drug therapy
Kidney Neoplasms - pathology
Mice
SciAdv r-articles
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Summary: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 -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- N]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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abp8293