Targeting ferroptosis in gefitinib-resistant HCC827 NSCLC cells using erastin.

Overcoming drug resistance remains essential for improving clinical outcomes in non-small cell lung cancer (NSCLC). This study explores the differential susceptibility of drug-resistant cancer cells, utilizing gefitinib (GEF)-resistant HCC827GR NSCLC cells as a model system. We observed that HCC827GR cells inherently display elevated levels of reactive oxygen species (ROS) and increased expression of ferroptosis-related markers when compared with GEF-sensitive cells. Accordingly, the HCC827GR lineage showed heightened responsiveness to erastin-mediated cytotoxicity, as determined by MTT and soft-agar assays. Our mechanistic investigations established that erastin treatment resulted in non-apoptotic cell death, accompanied by mitochondrial dysfunction and G2/M phase arrest in the cell cycle. In-depth analysis demonstrated that erastin notably raised intracellular iron and ROS concentrations and induced lipid peroxidation. Pretreatment with N-acetyl cysteine (NAC) validated the crucial involvement of ROS, and the use of ferrostatin-1 conclusively verified ferroptosis as the predominant mode of cell death. In summary, GEF-resistant HCC827GR cells exhibit increased sensitivity to erastin-induced ferroptosis compared with the parental line. This distinct vulnerability should be further studied as a potential therapeutic approach for targeting drug-resistant NSCLC.