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

// Mengfan Qi 1, 2, * , Ye Tian 3, 5, * , Wang Li 3, 5, * , Dan Li 3, 5 , Tian Zhao 3, 5 , Yuxin Yang 3, 5 , Qiwen Li 3, 5 , Sujun Chen 5 , Yan Yang 3, 5 , Zhixiong Zhang 3, 5 , Liang Tang 4 , Zhonghua Liu 1 , Bo Su 4 , Fei Li 6 , Yonghong Feng 1 , Ke Fei 2 , Peng Zhang 2 , Fan Zhang 1, 2, 3, 5 and Lei Zhang 2 1 Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 2 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 3 Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 4 The Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China 5 School of Life Science and Technology, Tongji University, Shanghai 200092, China 6 Department 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.