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

The ability of cancer cells to resist apoptotic death induced by chemotherapy and targeted therapies has been a primary impediment to achieving long-lasting clinical responses1. The plasticity of cancer cell states is gaining recognition as an important engine of tumor phenotypic heterogeneity, giving rise non-mutationally to subpopulations of cells that can contribute to therapy resistance, relapse, and disease progression2–4. Notably, acquisition of a high mesenchymal cell state via epithelial to mesenchymal transition (EMT) has been proposed to underlie resistance of cancer cells to targeted therapies5. Therapeutically exploitable vulnerabilities of cancer cells in such therapy-resistant states have not yet been identified5. A related challenge is posed by cancers derived from mesenchymal tissues, which suffer a similar dearth of rational therapeutic targets6. Here, we have discovered a vulnerability of cancer cells in a high-mesenchymal cell state mediated by the EMT master regulator and lipogenic factor ZEB17,8 to ferroptotic death induced by inhibition of pathways converging on the phospholipid glutathione peroxidase GPX4, which catalyzes the conversion of lipid hydroperoxides to lipid alcohols. Inhibition of GPX4 exhibits selectivity for both cancer cells in a therapy-resistant high-mesenchymal state observed in human tumors and cancer cells of mesenchymal origin. Importantly, GPX4 inhibitors affect high-mesenchymal state cancer cells at lower concentrations than non-transformed mesenchymal cells, pointing to a potential therapeutic window that is further expanded by the use of lipophilic antioxidants including vitamin E. Our results elucidate a pathway leading to a cell state frequently associated with therapy resistance in cancers and identify a novel dependency of cancer cells adopting this state on the activity of a druggable lipid hydroperoxidase.