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

Sci Adv. 2022 Dec 16;8(50):eabp8293. doi: 10.1126/sciadv.abp8293. Epub 2022 Dec 16.

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.

MeSH terms

  • Animals
  • 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

Substances

  • Glutaminase
  • Glutamine
  • Isocitrate Dehydrogenase