ArticleMolecular cancer research : MCR2019
Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC.
Article in Molecular cancer research : MCR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 39 citations in OpenAlex.
- CPS1: a multipurpose mitochondrial enzyme, bile protein, acute liver injury biomarker, and cytokine.Gut · 2026Review
- Predicting Clinical Outcomes and Immunotherapy Responses in Lung Adenocarcinoma Based on Nicotine Response Characteristics.Current medicinal chemistry · 2026Article
- CPS1-promoted the progression of lung adenocarcinoma via suppressing ammonia induced the activation of ROS/AMPK/P53/LKB1 signaling pathway.Scientific reports · 2025Article
- Long Non-Coding RNA LOC401312 Induces Radiosensitivity Through Upregulation of CPS1 in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2025Article
- Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.Cell reports · 2025Review
- Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.Nature communications · 2025Article
- PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma.Cancer & metabolism · 2024Article
- Construction and validation of a prognostic model for stemness-related genes in lung adenocarcinoma.Translational cancer research · 2024Article
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- Dysregulated Metabolism in EGFR-TKI Drug Resistant Non-Small-Cell Lung Cancer: A Systematic Review.Metabolites · 2022Review
- Molecular Typing Based on Oxidative Stress Genes and Establishment of Prognostic Characteristics of 7 Genes in Lung Adenocarcinoma.Oxidative medicine and cellular longevity · 2022Article
- Targeting glycolysis in non-small cell lung cancer: Promises and challenges.Frontiers in pharmacology · 2022Review
- The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes.International journal of molecular sciences · 2021Article
- Review
- Blockade of AMPK-Mediated cAMP-PKA-CREB/ATF1 Signaling Synergizes with Aspirin to Inhibit Hepatocellular Carcinoma.Cancers · 2021Article
- New insights into molecules and pathways of cancer metabolism and therapeutic implications.Cancer communications (London, England) · 2021Review
- Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways.Scientific reports · 2020Article
- Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.ACS medicinal chemistry letters · 2020Article
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Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.