title: Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine.
abstract: Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool North West Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool L69 7ZB, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Poursaitidis
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool North West Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool L69 7ZB, UK.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool North West Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool L69 7ZB, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Crighton
authors.affiliation: Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Christiaan
authors.initials: C
authors.lastname: Labuschagne
authors.affiliation: Centre for Cell Imaging, Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mason
authors.affiliation: Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Shira L
authors.initials: SL
authors.lastname: Cramer
authors.affiliation: Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Kendra
authors.initials: K
authors.lastname: Triplett
authors.affiliation: Division of Cancer CRUK Laboratories, 1st Floor ICTEM Building, Hammersmith Hospital Campus of Imperial College London, Du Cane Road, London W120NN, UK.
authors.forename: Rajat
authors.initials: R
authors.lastname: Roy
authors.affiliation: Division of Cancer CRUK Laboratories, 1st Floor ICTEM Building, Hammersmith Hospital Campus of Imperial College London, Du Cane Road, London W120NN, UK.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
authors.affiliation: Division of Cancer CRUK Laboratories, 1st Floor ICTEM Building, Hammersmith Hospital Campus of Imperial College London, Du Cane Road, London W120NN, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: Aeglea BioTherapeutics, Austin, TX 78746, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Rowlinson
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Everett
authors.initials: E
authors.lastname: Stone
authors.affiliation: School of Health Sciences, Liverpool Hope University, Hope Park Campus, Liverpool L16 9JD, UK. Electronic address: lambr@hope.ac.uk.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lamb
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001940:Breast / Q000166:cytology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D003553:Cystine / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D009857:Oncogenes; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase
chemical_list: D000596:Amino Acids; D003553:Cystine; D006861:Hydrogen Peroxide; D007501:Iron; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D066246:ErbB Receptors; D005978:Glutathione; D003545:Cysteine
keywords: EGFR; GPX4; MAPK; NOX4; ROS; ferroptosis; oncogene