Vitamin C selectively eliminates erlotinib-induced drug-tolerant persister cells via CERK and KRT82 regulation in EGFR-mutant non-small cell lung cancer

Abstract Despite the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) erlotinib in EGFR -mutant non-small cell lung cancer (NSCLC) patients, a subset of drug-tolerant persister (DTP) cells remains. While protein alterations unique to DTPs are crucial for their survival, the mechanisms remain unclear. Vitamin C has been proposed as an adjunct therapy, but its selective effects on DTPs and underlying anti-cancer mechanisms require further clarification. This study explored whether vitamin C co-treatment could selectively eliminate DTPs by targeting DTP-associated proteins. Proteomic profiling using mass spectrometry identified key molecular changes, from which candidate proteins sensitive to vitamin C were selected. Clinical data were also analyzed to link these proteins to survival outcomes in NSCLC patients. Co-treatment with vitamin C and erlotinib selectively suppressed DTP survival by suppressing CERK and KRT82. CERK was linked to DTP survival through AKT phosphorylation, while KRT82 was associated with changes in epithelial-mesenchymal transition (EMT) phenotype. Clinically, high keratin filament expression correlated with poorer prognosis in patients with EGFR -mutant NSCLC. Overall, our findings demonstrate that vitamin C effectively inhibits the survival of EGFR -mutant NSCLC cells by targeting CERK and KRT82, supporting its use as a safe and effective combination strategy to eliminate TKI-induced DTPs in NSCLC.