EGFR Tyrosine Kinase Inhibitors Activate Autophagy as a Cytoprotective Response in Human Lung Cancer Cells

Department of Medical Oncology, Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
PLoS ONE (Impact Factor: 3.23). 06/2011; 6(6):e18691. DOI: 10.1371/journal.pone.0018691
Source: PubMed


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.

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Available from: Yan Chen, Aug 12, 2014
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    • "Previous studies indicate that the PI3K/Akt/mTOR axis plays important roles in autophagy inhibition, especially in starvation-induced autophagy; inhibition of mTOR is one way to activate autophagy [22], [23]. Therefore, we tested whether LA or Epo affect the PI3K/Akt/mTOR pathway. "
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    PLoS ONE 07/2014; 9(7). DOI:10.1371/journal.pone.0103364 · 3.23 Impact Factor
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    • "Even so, autophagy seems to as a cytoprotective process and it was proposed as an alternative mechanism of drug resistance through promoting the tumor cell survival under unfavorable conditions. In lung cancer, several studies show that autophagy inhibition represents a promising approach to improve the efficacy of the treatment in patients with advanced non-small-cell lung cancer [22,23]. "
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    ABSTRACT: Beclin 1, a key regulator of autophagy, has been found to be aberrantly expressed in a variety of human malignancies. Herein, we employed immunohistochemistry (IHC) to detect the protein expression of Beclin 1 in non-small cell lung cancer (NSCLC) and paired normal adjacent lung tissues, and analyzed its clinicopathological/prognostic significance in NSCLC. Receiver operating characteristic (ROC) curve analysis was utilized to determine a cutoff point (>2 VS. ≤2) for Beclin 1 expression in a training set (n = 105). For validation, the ROC-derived cutoff value was subjected to analysis of the association of Beclin 1 with patients' clinical characteristics and outcome in a testing set (n = 111) and the overall patient cohort (n = 216). Our data showed that Beclin 1 was significantly lower in NSCLC tissues compared with the adjacent normal tissues, negatively associating with tumor recurrence rate (65.8% VS 32.3%; p < 0.001). In the testing set and the overall patient cohort, low expression of Beclin 1 showed significantly inferior overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) compared to high expression of Beclin 1. In the testing set and the overall patient cohort, the median duration of OS for patients with high and low expression of Beclin 1 was 108 VS. 24.5 months (p < 0.001) and 108 VS. 28 months (p < 0.001), respectively. Furthermore, low expression of Beclin 1 was also a poor prognostic factor within each stage of NSCLC patients. Multivariate analysis identified that Beclin 1 was an independent prognostic factor for NSCLC. Our findings in the present study provided evidence that Beclin 1 may thus emerge as an independent prognostic biomarker in this tumor entity in the future.
    PLoS ONE 11/2013; 8(11):e80338. DOI:10.1371/journal.pone.0080338 · 3.23 Impact Factor
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    • "However, in the presence of gefitinib, autophagy was further elevated in EGFR knockdown cells, as judged by increased LC3-II and cleaved GFP and decreased p62 levels. Similar findings were reported by Han et al. who showed that EGFR silencing resulted in increased LC3-II expression in gefitinib-treated lung cancer cells [18]. Interestingly, autophagy induction in MCF7-GFPLC3 cells by EGFR siRNA or gefitinib was not associated with changes in S6 phosphorylation, providing additional evidence that autophagy may be regulated by an mTORC1-independent mechanism in this cell line. "
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    PLoS ONE 10/2013; 8(10):e76503. DOI:10.1371/journal.pone.0076503 · 3.23 Impact Factor
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