ERK inhibition represses gefitinib resistance in non-small cell lung cancer cells

Mengfan Qi, Ye Tian, Wang Li, Dan Li, Tian Zhao, Yuxin Yang, Qiwen Li, Sujun Chen, Yan Yang, Zhixiong Zhang, Liang Tang, Zhonghua Liu, Bo Su, Fei Li, Yonghong Feng, Ke Fei, Peng Zhang, Fan Zhang, Lei Zhang

Research output: Contribution to journalArticle

Abstract

Gefitinib, an EGFR tyrosine kinase inhibitor, is used to treat non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, the resistance to gefitinib eventually emerges in most of the patients. To understand its mechanism, we generated two acquired gefitinib-resistant NSCLC cell lines. The resistant cells have slower growth rates, but are more resistant to apoptosis in the presence of gefitinib, compared with their sensitive counterparts. In addition, our genome-wide transcriptome analysis reveals unexpected pathways, particularly autophagy, are dysregulated in the gefitinib-resistant cells. Autophagy is significantly enhanced in resistant cells. Importantly, inhibition of autophagy reduces gefitinib resistance. Furthermore, the phosphorylation of ERK, the extracellular signal-regulated kinase, is activated in resistant cells. Inhibition of ERK phosphorylation abrogates gefitinib resistance by suppressing autophagy both in vitro and in vivo. These findings establish a link between ERK and autophagy in gefitinib resistance, and suggest that the ERK signaling may serve as the potentially therapeutic target for treating gefitinib resistance in NSCLC patients.

Original languageEnglish (US)
Pages (from-to)12020-12034
Number of pages15
JournalOncotarget
Volume9
Issue number15
DOIs
StatePublished - 2018

Keywords

  • Autophagy
  • ERK signaling
  • Gefitinib resistance
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Qi, M., Tian, Y., Li, W., Li, D., Zhao, T., Yang, Y., Li, Q., Chen, S., Yang, Y., Zhang, Z., Tang, L., Liu, Z., Su, B., Li, F., Feng, Y., Fei, K., Zhang, P., Zhang, F., & Zhang, L. (2018). ERK inhibition represses gefitinib resistance in non-small cell lung cancer cells. Oncotarget, 9(15), 12020-12034. https://doi.org/10.18632/oncotarget.24147