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Nature. 2017 Jul 27;547(7664):453-457. doi: 10.1038/nature23007. Epub 2017 Jul 5.

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

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Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th Street, Phoenix, Arizona 85004, USA.
Department of Dermatology, University of Zurich, University Hospital of Zurich, Wagistrasse 14, CH-8952, Schlieren, Zürich, Switzerland.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Moores Cancer Center &Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
Department of Biological Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, USA.
Massachusetts General Hospital Cancer Center, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Department of Biological Sciences, Department of Chemistry, Columbia University, 550 West 120th Street, New York, New York 10027, USA.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, USA.


Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

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