EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells

Weidong Han; Hongming Pan; Yan Chen; Jie Sun; Yanshan Wang; Jing Li; Weiting Ge; Lifeng Feng; Xiaoying Lin; Xiaojia Wang; Xian Wang; Hongchuan Jin

doi:10.1371/journal.pone.0018691

EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells

PLoS One. 2011;6(6):e18691. doi: 10.1371/journal.pone.0018691. Epub 2011 Jun 2.

Authors

Weidong Han¹, Hongming Pan, Yan Chen, Jie Sun, Yanshan Wang, Jing Li, Weiting Ge, Lifeng Feng, Xiaoying Lin, Xiaojia Wang, Xian Wang, Hongchuan Jin

Affiliation

¹ Department of Medical Oncology, Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy / drug effects*
Autophagy-Related Protein 5
Autophagy-Related Protein 7
Blotting, Western
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Erlotinib Hydrochloride
Gefitinib
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Lysosomes / drug effects
Lysosomes / metabolism
Lysosomes / ultrastructure
Microscopy, Confocal
Microscopy, Electron
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Phagosomes / drug effects
Phagosomes / metabolism
Phagosomes / ultrastructure
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / metabolism
Quinazolines / pharmacology*
RNA Interference
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / metabolism
Time Factors
Ubiquitin-Activating Enzymes / genetics
Ubiquitin-Activating Enzymes / metabolism

Substances

ATG5 protein, human
Autophagy-Related Protein 5
MAP1LC3A protein, human
Microtubule-Associated Proteins
Protein Kinase Inhibitors
Quinazolines
Erlotinib Hydrochloride
MTOR protein, human
ErbB Receptors
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases
ATG7 protein, human
Autophagy-Related Protein 7
Ubiquitin-Activating Enzymes
Gefitinib