Src and the
mammalian target of rapamycin (mTOR) signaling are commonly activated in
non-small cell lung cancer (NSCLC) and hence potential targets for
chemotherapy. Although the combined use of Src inhibitor
Dasatinib with other chemotherapeutic agents has shown superior efficacy for
cancer treatment, the mechanisms that lead to enhanced sensitivity of
Dasatinib are not completely understood. In this study, we found that
Rapamycin dramatically enhanced
Dasatinib-induced cell growth inhibition and cell cycle G1 arrest in human
lung adenocarcinoma A549 cells without affecting apoptosis. The synergistic effects were consistently correlated with the up-regulation of
cyclin-dependent kinases inhibitor
proteins, including p16, p19, p21, and p27, as well as the repression of Cdk4 expression and nuclear translocation. Mechanistic investigations demonstrated that FoxO1/FoxO3a and
p70S6K/4E-BP1, the molecules at downstream of Src-PI3K-Akt and mTOR signaling, were significantly suppressed by the combined use of
Dasatinib and
Rapamycin. Restraining Src and mTOR with
small interfering RNA in A549 cells further confirmed that the Src/PI3K/mTOR Pathway played a crucial role in enhancing the anticancer effect of
Dasatinib. In addition, this finding was also validated by a series of assays using another two NSCLC cell lines, NCI-H1706 and NCI-H460. Conclusively, our results suggested that the combinatory application of Src and
mTOR inhibitors might be a promising therapeutic strategy for NSCLC treatment.