Therapy-resistant cancer cell states identified across diverse contexts are selectively vulnerable to ferroptotic cell death induced by inhibition of lipid peroxidase pathways converging on GPX4. Cancer cells can assume different biological states, which can affect their resistance to therapies. A mesenchymal phenotype has been associated with drug resistance but the mechanism behind this state is not well understood. Stuart Schreiber and colleagues now show that tumour cells with a mesenchymal phenotype are selectively sensitive to inhibition of GPX4, an enzyme that alters lipid metabolism. GPX4 dissipates lipid peroxides and therefore prevents the iron-mediated reactions which induce ferroptotic cell death. These findings offer new perspectives on targeting cancers that have undergone a transition to a mesenchymal state to evade other therapeutic agents. Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness1,2,3,4. 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 understood1,2,3,4,5,6. 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 peroxides7,8. 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 enzymes8,9. 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 death8. 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.

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