Identifying strategies to target the metabolic flexibility of tumours.

Nature Metabolism
Andres Mendez-LucasMariia Yuneva

Abstract

Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours considerably delays tumourigenesis, glutamine catabolism continues, owing to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated for by glycolysis. Thus, co-inhibition of Gls1 and hexokinase 2 significantly affects Krebs cycle activity and tumour formation. Finally, the inhibition of biosynthesis of either serine (Psat1-KO) or fatty acid (Fasn-KO) is compensated for by uptake of circulating nutrients, and dietary restriction of both serine and glycine or fatty acids synergistically suppresses tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate that either pharmacological or dietary targeting of metabolic compensatory mechan...Continue Reading

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Datasets Mentioned

BETA
GSE129013

Methods Mentioned

BETA
transfection
nuclear magnetic resonance
NMR
xenografts
xenograft
transgenic
gene knockout
electrophoresis
X-ray

Clinical Trials Mentioned

NCT02223247
NCT03032484
NCT02980029
NCT03179904

Software Mentioned

Bruker TopSpin
Affymetrix package
IncuCyte Live - Cell
TraceFinder
hmbcf3gpndqf
Bioconductor
Topspin
noesygpr1d
MassHunter Quantitative Analysis
LCS Lite

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