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Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds



Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds



Oncology Reports 29(6): 2486-2492



The epidermal growth factor receptor (EGFR) signaling pathway is widely activated in non-small cell lung cancer (NSCLC). However, only a subset of patients with NSCLC is sensitive to EGFR tyrosine kinase inhibitors (TKIs), particularly those with activating EGFR mutations. The mammalian target of rapamycin (mTOR) is another key intracellular kinase that plays an important role in the onset and progression of many types of human cancers and has been proven to be linked with primary resistance to EGFR inhibitors. We performed this study to investigate the combined inhibitory effect of the mTOR inhibitor RAD001 and the EGFR-TKI gefitinib in three EGFR wild-type NSCLC cell lines: A549 (PIK3CA wild‑type), NCI-H460 (PIK3CA mutant) and NCI-H661 (PIK3CA wild-type). All cell lines demonstrate a poor response to gefitinib, but have a different genetic status for PIK3CA. We used MTT assays to measure cell proliferation. Flow cytometry was used to assess the effects on apoptosis and cell cycle arrest. Immunoblot analysis was used to evaluate the expression of downstream proteins. Treatment of RAD001 alone showed dose-dependent growth inhibition in all three cell lines. The combination of gefitinib and RAD001 resulted in synergistic growth inhibition in NCI-H460 cells, but only an additive inhibitory effect on A549 and NCI-H661 cells. Exposure to the combination of RAD001 and gefitinib led to a significant reduction in phosphorylated AKT levels in NCI-H460 cells; however, this was not noted in the other two cell lines. In conclusion, our data indicate that the dual inhibition of the EGFR/mTOR pathways may be a promising approach to treat EGFR wild-type NSCLC; however, this may be dependent on the PIK3CA mutation status.

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Accession: 052179606

Download citation: RISBibTeXText

PMID: 23525575

DOI: 10.3892/or.2013.2357


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