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

TLDR: 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 is identified.

Abstract: 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.