Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer.
Highlights
Lung cancer is the leading cause of cancer deaths worldwide [1]
epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) induce autophagy in lung cancer cells To evaluate the activation of autophagy by EGFR-TKIs, the conversion of light chain 3 (LC3)-I into LC3-II before and after TKIs treatment was determined by western blotting analysis
In A549 and NCIH1299 cells, both gefitinib and erlotinib can induce the switch of LC3-I to LC3-II in the dose and time dependent manner, indicating that autophagy might be activated by both TKIs (Figure 1A and B)
Summary
Chemotherapy is still not effective enough for patients with advanced non–small-cell lung cancer (NSCLC) and the response rate is only 20% to 35% with a median survival of 10 to 12 months [2,3]. By inhibiting the tyrosine kinase activity of EGFR, two tyrosine kinase inhibitors (TKIs) named gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva, Genentech) have been developed for the treatment of NSCLC. Gefitinib and erlotinib can inhibit tumor growth both in vitro and in vivo. Both EGFR-TKIs showed good tolerability and antitumor activity in NSCLC patients with disease progressing after first line platinum-based chemotherapy [5,8,9]. The mechanism is still largely unknown EGFR mutations have been proposed to be one of mechanisms to influence the sensitivity of EGFR to these inhibitors [10,11]
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