Oncotarget

Research Papers:

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 and Lei Zhang _

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Oncotarget. 2018; 9:12020-12034. https://doi.org/10.18632/oncotarget.24147

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Abstract

Mengfan Qi1,2,*, Ye Tian3,5,*, Wang Li3,5,*, Dan Li3,5, Tian Zhao3,5, Yuxin Yang3,5, Qiwen Li3,5, Sujun Chen5, Yan Yang3,5, Zhixiong Zhang3,5, Liang Tang4, Zhonghua Liu1, Bo Su4, Fei Li6, Yonghong Feng1, Ke Fei2, Peng Zhang2, Fan Zhang1,2,3,5 and Lei Zhang2

1Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

3Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

4The Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China

5School of Life Science and Technology, Tongji University, Shanghai 200092, China

6Department of Biology, New York University, New York, NY 10003, USA

*These authors contributed equally to this work

Correspondence to:

Lei Zhang, email: 13816121971@163.com

Fan Zhang, email: fzhang@tongji.edu.cn

Keywords: non-small cell lung cancer; gefitinib resistance; ERK signaling; autophagy

Received: September 06, 2017     Accepted: January 03, 2018     Published: January 10, 2018

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.


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