Pharmacological blockade of oncogenic MAPK activators drives resistance to cystine deprivation with lipid redox remodeling.

Targeted therapies disrupt oncogenic signaling while inducing adaptive metabolic rewiring for cancer cell survival. However, the roles of acute metabolic shifts remain poorly understood. Here, we showed that inhibiting EGFR, KRAS, or BRAF drove resistance to cystine deprivation-induced ferroptosis in cancer cells harboring each driver mutation. Resistance to cystine deprivation emerged within 24 h of drug treatment and persisted during prolonged 9-day exposure. However, acquiring drug resistance during the 2-month drug exposure abolished the resistance to cystine deprivation, coupled with reactivation of MAPK signaling. Mechanistically, GPX4, which was induced by drug treatment, was crucial to prevent ferroptosis despite a reduction in intracellular cysteine and glutathione levels during cystine deprivation. Additionally, the oncogenic inhibitors altered ALDH isozyme expression profiles, potentially inducing resistance to 4-hydroxynonenal, which is a lipid aldehyde associated with ferroptosis. Our findings identify a novel cellular adaptation mechanism to oncogenic signaling inhibition, providing mechanistic insights into how cancer cells adjust their lipid redox balance during therapy.