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.