mTOR 抑制剂反馈激活Mnk (MAP kinase integrating kinase, Mnk)依赖性eIF4E(eukaryotic translation initiation factor 4E, eIF4E)的磷酸化，降低其抗肿瘤疗效。Mnk 1是eIF4E磷酸化的唯一激酶，磷酸化eIF4E抑制细胞凋亡, 促进肿瘤增殖。我们前期研究发现mTOR抑制剂RAD001（RAD）增加肺癌的磷酸化eIF4E。Mnk1抑制剂CGP57380（CGP）抑制eIF4E磷酸化，增加DR5和下调c-FLIP的表达。CGP联合 RAD诱导肺癌细胞凋亡，增加抗肿瘤效应。本项目主要研究CGP抑制eIF4E磷酸化，经何种机制调控DR5和c-FLIP的表达，诱导细胞凋亡，增加RAD治疗非小细胞肺癌的疗效。项目的完成将首次阐明CGP可能通过死亡受体通路诱导细胞凋亡增效RAD的分子机制，具有重要理论意义。

mTOR （mammalian target of rapamycin，mTOR）inhibitors increase Mnk (MAP kinase integrating kinase, Mnk)-dependent phosphorylation of eIF4E (eukaryotic translation initiation factor 4E, eIF4E) through mTOR inhibition-induced feedback mechanism and decrease mTOR inhibitor's anticancer activity. Phosphorylation of eIF4E is specifically catalyzed by mitogen-activated protein kinase Mnk1. Phosphorylated eIF4E plays a crucial role in inhibiting cell apoptosis and causing cell proliferation. Our findings indicate increase the expression of phosphorylated eIF4E in the non small cell lung cancer (NSCLC) xenografts and cell lines with RAD001-treated. Our data also demonstrated Mnk inhibitor CGP57380 is capable of inhibiting the phosphorylation of eIF4E and inducing high expression of DR5 (death receptor 5) and down-regulation of c-FLIP(cellular FLICE-like inhibitory protein) in NSCLC cell lines. Combination CGP57380 and RAD001 enhance the antitumor activity by inducing apoptosis and suppressing the proliferation of cultured human NSCLC cell lines. The most important part of the research project is to investigate the molecular mechanism of enhancing the anticancer effect of NSCLC with RAD001 treatment and CGP 57380 selectively inhibited the phosphorylation of eIF4E and inducing NSCLC cell apoptosis through induction of DR5 and down-regulation of c-FLIP protein. The achievement of the novel research project may be first to elucidate the molecular mechanism of the synergistic anticancer activity of CGP57380 combined with RAD001 by inducing apoptosis of NSCLC cells through the death receptor pathway. Therefore, the project might have theoretical significance and important implications for clinical applications.