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.
Teaser Glutamine fuels the TCA cycle and amidotransferase pathways in clear cell renal cell carcinoma.
Competing Interest Statement
Competing interests: R.J.D. is a scientific advisor for Agios Pharmaceuticals and Vida Ventures, and a founder and advisor for Atavistik Bioscience. J.B. is an employee/paid consultant for Arrowhead, Calithera, Esai, Exelixis, and Johnson & Johnson and reports receiving commercial research grants from Arrowhead. J.B. and X.S. have a patent application on [18F]PT2385. I.P. reports personal fees from Bayer Healthcare and Health Tech International, personal fees for serving in an Advisory Committee for Merck, and others from Philips Healthcare, all outside of the submitted work. All other authors declare they have no competing interests.
Footnotes
As per the guidelines of the journal at which this manuscript is under consideration, this is the original submitted version of the paper.