Clathrin-mediated EGFR endocytosis as a potential therapeutic strategy for overcoming primary resistance of EGFR TKI in wild-type EGFR non-small cell lung cancer

Boyeon Kim, Young Soo Park, Jae Sook Sung, Jong Won Lee, Saet Byeol Lee, Yeul Hong Kim

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Objectives: Oncogenic alterations of epidermal growth factor receptor (EGFR) signaling are frequently noted in non-small cell lung cancer (NSCLC). In recent decades, EGFR tyrosine kinase inhibitors (TKIs) have been developed, although the therapeutic efficacy of these inhibitor is restricted to EGFR-mutant patients. In this study, we investigated that clathrin-mediated EGFR endocytosis hampers the effects of gefitinib and sustains NSCLC cells with wild-type EGFR. Materials and Methods: NSCLC cell lines (H358, Calu-3, SNU-1327, and H1703) were stimulated with the EGF and treated with gefitinib and endocytosis inhibitors (phenylarsine oxide (PAO) and Filipin III). Growth inhibition and apoptosis were evaluated. Immunofluorescence, immunoprecipitation, and western blot assay were performed to investigate EGFR endocytosis and determine the signaling pathway. Xenograft mouse models were used to verify the combination effect of gefitinib and PAO in vivo. Results: We confirmed the differences in EGFR endocytosis according to gefitinib response in wild-type EGFR NSCLC cell lines. EGFR in gefitinib-sensitive and -refractory cell lines tended to internalize through distinct routes, caveolin-mediated endocytosis (CVE), and clathrin-mediated endocytosis (CME). Interestingly, while suppressing CME and CVE did not affect cell survival in sensitive cell lines significantly, CME inhibition combined with gefitinib treatment decreased cell survival and induced apoptosis in gefitinib-refractory cell lines. In addition, blocking CME in the refractory cell lines led to downregulate of p-STAT3 and inhibit nuclear localization of STAT3 in vivo, combination treatment with gefitinib and a CME inhibitor resulted in tumor regression accompanying apoptosis in xenograft mouse models. Conclusion: Clathrin-mediated EGFR endocytosis contribute primary resistance of gefitinib treatment and CME inhibition combined with gefitinib could be an option in treatment of wild-type EGFR NSCLC.

Original languageEnglish
Pages (from-to)372-385
Number of pages14
JournalCancer medicine
Issue number1
Publication statusPublished - 2021 Jan

Bibliographical note

Publisher Copyright:
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.


  • clathrin mediated endocytosis
  • gefitinib
  • non-small cell lung cancer
  • resistance

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research


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