👤 Rosanna Di Paola

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. Show less

Liver X receptor alpha (LXRalpha) and LXRbeta are members of the nuclear receptor superfamily of ligand-activated transcription factors. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of spinal cord injury (SCI). SCI was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy in mice. Treatment with T0901317, 1 and 6 h after the SCI, significantly decreased (i) the degree of spinal cord inflammation and tissue injury (histological score); (ii) neutrophil infiltration (myeloperoxidase activity); (iii) inducible nitric oxide synthase expression; (iv) nitrotyrosine, lipid peroxidation, and poly-ADP-ribose formation; (v) pro-inflammatory cytokines expression; (vi) nuclear factor-kappa B activation; and (vii) apoptosis (terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, FAS ligand, Bax, and Bcl-2 expression). Moreover, T0901317 significantly ameliorated the loss of limb function (evaluated by motor recovery score). These data suggest that LXR ligand may be useful in the treatment of inflammation associated with SCI. Show less