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

Kaushik, AK; Tarangelo, A; Boroughs, LK; Ragavan, M; Zhang, Y; Wu, CY; Li, X; Ahumada, K; Chiang, JC; Tcheuyap, VT; Saatchi, F; Do, QN; Yong, C; Rosales, T; Stevens, C; Rao, AD; Faubert, B; Pachnis, P; Zacharias, LG; Vu, H; Cai, F; Mathews, TP; Genovese, G; Slusher, BS; Kapur, P; Sun, X; Merritt, M; Brugarolas, J; Deberardinis, RJ

Author(s): Kaushik, AK; Tarangelo, A; Boroughs, LK; Ragavan, M; Zhang, Y; Wu, CY; Li, X; Ahumada, K; Chiang, JC; Tcheuyap, VT; Saatchi, F; Do, QN; Yong, C; Rosales, T; Stevens, C; Rao, AD; Faubert, B; Pachnis, P; Zacharias, LG; Vu, H; Cai, F; Mathews, TP; Genovese, G; Slusher, BS; Kapur, P; Sun, X; Merritt, M; Brugarolas, J; Deberardinis, RJ;
Details: Publication Year 2022-12-16,Volume 8,Issue #50,Page eabp8293
Journal Title: Science Advances
Publication Type: Research article
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-(15)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.
Keywords: Humans; Mice; Animals; *Carcinoma, Renal Cell/drug therapy/metabolism; Glutaminase/therapeutic use; *Kidney Neoplasms/drug therapy/pathology; Glutamine/metabolism; Isocitrate Dehydrogenase
Department(s): Laboratory Research; Medical Oncology
PubMed ID: 36525494
Publisher's Version: https://doi.org/10.1126/sciadv.abp8293
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.abp8293
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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