Study The Relationship Between PI3K/AKT/mTOR Signaling Pathways And The Intrinsic Resistance Of Nasopharyngeal Carcinoma CNE1-LMP1Cells To Gefitinib

Background and purpose:Previous studies show,EGFR in a variety of tumors in thepresence of high expression.EGFR-TKIs are effective to a variety of high expression ofEGFR tumor,including NSCLCs.The expression of EGFR and the prognosis ofnasopharyngeal carcinoma was negatively correlated.,while the epidermal growth factorreceptor tyrosine kinase inhibitors(EGFR-TKIs) gefitinib has poor efficacy on theprogressed and recurrent nasopharyngeal carcinoma.The combination of EGFR-TKIs andmTOR inhibitor is confirmed has synergistic effect in NSCLC,SCCHN,GBM,pancreaticand prostate cancer and so on.In this study we aims to explore the effects of combinedadministration of gefitinib(Iressa) and everolimus(RAD001) on the nasopharyngealcarcinoma cell line CNE1-LMP1and elucidate their molecular mechanism.To studywhether there is a correlation between PI3K/AKT/mTOR pathway and the intrinsicresistance of nasopharyngeal carcinoma to gefitinib.Methods:Human nasopharyngeal carcinoma cell CNE1-LMP1was treated withgefitinib and everolimus alone or in combination.MTT assay was utilized to measure theinhibition of cell proliferation in each group.The apoptosis of cells and cell cycle weredetected by flow cytometry.Western bloting was performed to detect the protein expression of phosphorylated Akt(p-Akt) and phosphorylated p70S6K(p-p70S6K).Results:Both gefitinib and everolimus can inhibit the cell proliferation and induce thecell apotosis of CNE1-LMP1cells in a dose-dependent manner in vitro.The cominedtreatment with gefitinib and everolimus result in a synergistic effect in inhibiting cellproliferation, inducing apoptosis and decreasing the expressions of p-Akt,p-p70S6Kproteins.Cell cycle studies show that both gefitinib and combination group can induceG0/G1arrest,and the stronger effect of the combination group.Conclusions:Gefitinib and everolimus have better synergistic effects.The possiblemechanism to work together is to inhibit CNE1-LMP1cell proliferation, apoptosis,reducing the level of expression of proliferation-related signaling protein.Preliminaryconfirm that PI3K/AKT/mTOR signaling pathway is related to the intrinsic resistance ofnasopharyngeal carcinoma to gefitinib.Combined treatment has a potential in the treatmentof nasopharyngeal carcinoma in clinic.