title: EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR.
abstract: 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.
authors.affiliation: BK21 Plus program, Korea University Anam Hospital, Seongbuk-gu, Seoul, Republic of Korea.
authors.forename: Ukhyun
authors.initials: U
authors.lastname: Jo
authors.forename: Kyong Hwa
authors.initials: KH
authors.lastname: Park
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Whang
authors.forename: Jae Sook
authors.initials: JS
authors.lastname: Sung
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Won
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.forename: Yeul Hong
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D034281:Dynamins / Q000037:antagonists & inhibitors; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C509763:Rab25 protein, human; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020691:rab GTP-Binding Proteins; D034281:Dynamins; D000077156:Gefitinib