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

Pham-Danis, Catherine; Gehrke, Sarah; Danis, Etienne; Rozhok, Andrii I; Daniels, Michael W; Gao, Dexiang; Collins, Christina; Paola, José T Di; D'Alessandro, Angelo; DeGregori, James

Pham-Danis, Catherine; Gehrke, Sarah; Danis, Etienne; Rozhok, Andrii I; Daniels, Michael W; Gao, Dexiang; Collins, Christina; Paola, José T Di; D'Alessandro, Angelo; DeGregori, James.

Afiliación

Pham-Danis C; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Gehrke S; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Danis E; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Rozhok AI; Department of Dermatology, Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Daniels MW; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Gao D; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Collins C; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Paola JTD; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
DeGregori J; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado. james.degregori@ucdenver.edu.

Mol Cancer Res ; 17(6): 1351-1364, 2019 06.

Article en En | MEDLINE | ID: mdl-30808730

RESUMEN

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.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/genética; Carcinoma de Pulmón de Células no Pequeñas/metabolismo; Neoplasias Pulmonares/genética; Neoplasias Pulmonares/metabolismo; Mutación/genética; Urea/metabolismo; Carbamoil-Fosfato Sintasa (Amoniaco)/genética; Línea Celular; Línea Celular Tumoral; Proliferación Celular/genética; Respiración de la Célula/genética; Receptores ErbB/genética; Glucólisis/genética; Células HEK293; Humanos; Metabolómica/métodos; Mitocondrias/genética; Pronóstico; Pirimidinas/metabolismo; Transducción de Señal/genética

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Urea / Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cancer Res Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos

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