AI Article Synopsis

  • Mutations in oncogenes and tumor suppressor genes create specific metabolic needs for tumor cells, particularly in non-small cell lung cancer (NSCLC) driven by EGFR signaling.
  • Researchers used functional genomics and metabolomics to find that when EGFR is inhibited in NSCLC cells, these cells become reliant on the urea cycle and the enzyme CPS1.
  • Combining CPS1 knockdown with EGFR inhibition significantly hampers cell growth and metabolism, highlighting the urea cycle as a potential target for combined therapies in treating EGFR-driven NSCLC.

Article 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 databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR. IMPLICATIONS: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFR-driven NSCLC.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548670PMC
http://dx.doi.org/10.1158/1541-7786.MCR-18-1068DOI Listing

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