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

DeBerardinis, R. J.; Kaushik, A.; Burroughs, L. K.; Tarangelo, A.; Ragavan, M.; Wu, C.-Y.; Li, X.; Ahumada, K.; Tcheuyap, V. T.; Saatchi, F.; Do, Q.; Yong, C.; Rosales, T.; Stevens, C.; Rao, A. D.; Faubert, B.; Pachnis, P.; Zacharias, L. G.; Vu, H.; Cai, F.; Mathews, T. P.; Slusher, B. S. P.; Kapur, P.; Sun, X.; Merritt, M.; Brugarolas, J.; Zhang, Y.; Chiang, J.-C.; Genovese, G.

doi:10.1101/2022.10.31.514397

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bioRxiv · 10.1101/2022.10.31.514397

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

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Abstract

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed metabolism in patient-derived xenografts (tumorgrafts) from diverse forms of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engage in oxidative and reductive glutamine metabolism. We used several approaches to suppress glutamine metabolism and test the effect on tumor growth. Genetic silencing of isocitrate dehydrogenase-1 or -2 impaired reductive labeling of TCA cycle intermediates and suppressed tumor growth. Glutaminase inhibition resulted in modest growth suppression and variable effects on glutamine metabolism in vivo. 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. 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. TeaserGlutamine fuels the TCA cycle and amidotransferase pathways in clear cell renal cell carcinoma.

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DeBerardinis, R. J., Kaushik, A., Burroughs, L. K., Tarangelo, A., Ragavan, M., Wu, C.-Y., Li, X., Ahumada, K., Tcheuyap, V. T., Saatchi, F., Do, Q., Yong, C., Rosales, T., Stevens, C., Rao, A. D., Faubert, B., Pachnis, P., Zacharias, L. G., Vu, H., Cai, F., Mathews, T. P., Slusher, B. S. P., Kapur, P., Sun, X., Merritt, M., Brugarolas, J., Zhang, Y., Chiang, J.-C., Genovese, G.. 2022-11-01. In-vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. https://doi.org/10.1101/2022.10.31.514397

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