Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC

Molecular Cancer Research : MCR
Catherine Pham-DanisJames DeGregori

Abstract

Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non-small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available ...Continue Reading

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Citations

Nov 12, 2020·Cancer Communications·Zhenye TangJinfang Zhang
Jan 26, 2021·The Journal of Biological Chemistry·Junjie YueZhuojuan Luo
Feb 6, 2020·Cell Chemical Biology·Shihua YaoDavid M Bolduc
Jun 20, 2020·ACS Medicinal Chemistry Letters·Alan RolfeDavid M Bolduc
Sep 2, 2021·Molecular Cell·Emma HajajAyelet Erez

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