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

Targeting metabolic vulnerabilities continues to be suggested like a therapeutic strategy in kidney cell carcinoma (RCC). Here, we examined the metabolic process of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant obvious cell RCC (ccRCC) retained metabolic options that come with human ccRCC and involved in oxidative and reductive glutamine metabolic process. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acidity (TCA) cycle intermediates in vivo and covered up development of tumors produced by tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine towards the TCA cycle and led to modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities using the amidotransferase inhibitor JHU-083 also reduced tumor development in both immunocompromised and immunocompetent rodents. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, possibly explaining why it’s been difficult to achieve therapeutic responses in patients by inhibiting glutaminase.