Oncogenic alterations of
epidermal growth factor receptor (EGFR) signaling are frequently observed in
lung cancer patients with worse differentiation and poor prognosis. However, the therapeutic efficacy of EGFR-
tyrosine kinase inhibitors (TKIs) is currently limited in selected patients with EGFR mutations. Therefore, in this study, we investigated the potential molecular mechanism that contributes to cell viability and the response of
gefitinib, one of the EGFR-TKIs, in
lung cancer models with wide-type EGFR (wtEGFR). Interestingly, we found that
EGF-induced EGFR endocytosis is existed differently between
gefitinib-sensitive and -insensitive
lung cancer cell lines. Suppressing EGFR endocytos decreased cell viability and increased apoptotic cell death in
gefitinib-insensitive
lung cancer with wtEGFR in vitro and in vivo. In addition, we found that Rab25 was differentially expressed in between
gefitinib-sensitive and -insensitive
lung cancer cells. Rab25 knockdown caused the changed EGFR endocytosis and reverted the
gefitinib response in
gefitinib-sensitive
lung cancer with wtEGFR in vitro and in vivo. Taken together, our findings suggest a novel insight that EGFR endocytosis is a rational therapeutic target in
lung cancer with wtEGFR, in which the combined efficacy with
gefitinib is expected. Furthermore, we demonstrated that Rab25 plays an important role in EGFR endocytosis and
gefitinib therapy.