Abstract
Acquired resistance to epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical obstacle in the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). EHD1, a protein of the C-terminal Eps15 homology domain-containing (EHD) family, plays a role in regulating endocytic recycling, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we found that a lower EHD1 expression improved both EGFR-TKIs sensitivity, which is consistent with a lower CD133 expression, and progression-free survival in NSCLC patients. The overexpression of EHD1 markedly increased erlotinib resistance and lung cancer cell stemness in vitro and in vivo. Moreover, we demonstrated that miR-590 targeted the 3'-UTR of EHD1 and was regulated by NK-κB, resulting in downregulated EHD1 expression, increased erlotinib sensitivity and repressed NSCLC cancer stem-like properties in vitro and in vivo. We found that EHD1 was an important factor in EGFR-TKI resistance and the cancer stem-like cell phenotype of lung cancer, and these results suggest that targeting the NF-κB/miR-590/EHD1 pathway has potential therapeutic promise in EGFR-mutant NSCLC patients with acquired EGFR-TKI resistance.