Depletion of RNF25 prominently impaired the proliferation of gefitinib-resistant NSCLC PDCs, as well as H1650 cells in the presence of gefitinib, while augmentation of RNF25 expression in gefitinib-sensitive EGFR-mutant cells rendered them more refractory to gefitinib treatment. Here, RNF25 is linked to non-small cell lung carcinoma.