Dependency of a Therapy-Resistant State of Cancer Cells on a Lipid Peroxidase Pathway

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

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Transdifferentiation
  • Drug Resistance, Neoplasm / genetics
  • Epithelial-Mesenchymal Transition
  • Glutathione Peroxidase / metabolism*
  • Humans
  • Iron / metabolism
  • Lipid Peroxidation / drug effects*
  • Lipid Peroxides / metabolism
  • Male
  • Melanoma / drug therapy
  • Melanoma / enzymology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mesoderm / drug effects
  • Mesoderm / enzymology
  • Mesoderm / metabolism
  • Mesoderm / pathology
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proteomics
  • Proto-Oncogene Proteins B-raf / genetics
  • Reproducibility of Results
  • Zinc Finger E-box-Binding Homeobox 1 / genetics

Substances

  • Cadherins
  • Lipid Peroxides
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • Iron
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Glutathione Peroxidase
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf