Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Ioannis Poursaitidis, Xiaomeng Wang, Thomas Crighton, Christiaan Labuschagne, David Mason, Shira L. Cramer, Kendra Triplett, Rajat Roy, Olivier E. Pardo, Michael J. Seckl, Scott W. Rowlinson, Everett Stone, Richard F. Lamb
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.

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Teaser

Poursaitidis et al. show that EGFR and BRAF mutant cells are sensitive to ferroptosis. Sensitivity was related to activation of MAPK signaling and the generation and release of hydrogen peroxide. To show that this sensitivity can be exploited therapeutically, growth of an EGFR mutant NSCLC xenograft was inhibited by a cyst(e)ine-degrading enzyme.


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