Biological Sciences Division
Published December 16, 2022 | Version v1
Journal article Open

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

Creators

  • 1. University of Texas Southwestern Medical Center
  • 2. St. Jude Children's Research Hospital
  • 3. University of Cambridge
  • 4. University of Melbourne
  • 5. University of Chicago
  • 6. MD Anderson Cancer Center, Houston
  • 7. Johns Hopkins University

Description

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The tumorgrafts can be provided by J.B. pending scientific review and a completed material transfer agreement. Requests for the tumorgrafts should be submitted to: KCPDRA@utsouthwestern.edu. JHU-083 can be provided by B.S.S. pending scientific review and a completed material transfer agreement. Requests for JHU-083 should be submitted to: bslusher@jhmi.edu. CB-839 was provided through a material transfer agreement by Calithera Biosciences (authorized representative, T. Davis, tdavis@calithera.com).

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Additional details

Identifiers

DOI
10.1126/sciadv.abp8293
Other
oai:uchicago.tind.io:11040

Funding

National Institutes of Health
4K00CA234650
Howard Hughes Medical Institute
National Cancer Institute
R35CA22044901
Kidney Cancer Association
Kidney Cancer Association
P50CA19651602

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine