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Identifying strategies to target the metabolic flexibility of tumours

By Andrés Méndez-Lucas, Wei Lin, Paul C. Driscoll, Nathalie Legrave, Laura Novellasdemunt Vilaseca, Chencheng Xie, Mark Charles, Zena Wilson, Neil P. Jones, Stephen Rayport, Manuel Rodríguez-Justo, Vivian Li, James I MacRae, Nissim Hay, Xin Chen, Mariia Yuneva

Posted 07 Jan 2020
bioRxiv DOI: 10.1101/2020.01.06.896571 (published DOI: 10.1038/s42255-020-0195-8)

Plasticity of cancer metabolism can be a major obstacle for efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify and quantify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that glutaminase isoform Gls2, expressed in normal liver, compensates for the deletion of Gls1 isoform expressed in tumours. Inhibiting both glutaminases significantly delays tumourigenesis but does not completely block glutamine catabolism through the Krebs cycle. We reveal that glutamine catabolism is then driven by amidotransferases. Consistently, the synergistic effect of glutaminase and amidotransferase inhibitors on proliferation of mouse and human tumour cells is observed in vitro and in vivo . Furthermore, when Gls1 is deleted the Krebs cycle activity and tumour formation can also be significantly affected if glycolysis is co-inhibited (Gls1KO/ Hk2KO ). Finally, the inhibition of either serine ( Psat1 KO) or fatty acid ( Fasn KO) biosynthesis can be compensated by uptake of circulating nutrients. Thus, removing these nutrients from the diet produces synergistic effects on suppression of tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate how targeting compensatory mechanisms can improve a therapeutic outcome.

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