%0 Figure %A Yuan, Man %A Xu, Lin-feng %A Zhang, Juan %A Kong, Si-yuan %A Wu, Man %A Lao, Yuan-zhi %A Zhou, Hua %A Zhang, Li %A Xu, Hongxi %D 2019 %T Image_1_SRC and MEK Co-inhibition Synergistically Enhances the Anti-tumor Effect in Both Non-small-cell Lung Cancer (NSCLC) and Erlotinib-Resistant NSCLC.JPEG %U https://frontiersin.figshare.com/articles/figure/Image_1_SRC_and_MEK_Co-inhibition_Synergistically_Enhances_the_Anti-tumor_Effect_in_Both_Non-small-cell_Lung_Cancer_NSCLC_and_Erlotinib-Resistant_NSCLC_JPEG/9169016 %R 10.3389/fonc.2019.00586.s001 %2 https://frontiersin.figshare.com/ndownloader/files/16707551 %K non-small-cell lung cancer %K MEK and SRC inhibitor %K trametinib %K bosutinib %K synergistic effect %X

Non-small-cell lung cancer (NSCLC) is the predominant form of lung cancer, and it is regulated by a complex signal transduction network. Single-agent targeted therapy often results in acquired resistance, which leads to treatment failure. In this study, we demonstrated that a combination of the kinase inhibitors trametinib and bosutinib can synergistically suppress the growth of NSCLC by inhibiting both the mitogen-activated protein kinase (MAPK) and proto-oncogene tyrosine-protein kinase (SRC) pathways. The combination was profiled against a panel of 22 NSCLC cell lines, including one erlotinib-resistant cell line, and this combination was found to show synergistic effects against 16 cell lines. NSCLC cell lines (HCC827, HCC827-erlotinib-resistant, and H1650) were treated with trametinib, bosutinib, or a combination of these drugs. The drug combination inhibited colony formation and induced cell apoptosis. A mechanism study showed that the phosphorylation of multiple kinases in the epidermal growth factor receptor (EGFR) signaling pathway in NSCLC was down-regulated. In addition, the combination significantly attenuated tumor growth of HCC827 xenografts with low toxicity. Our findings provide a theoretical basis for further study of the combination of MAPK and SRC pathway inhibitors in NSCLC, especially in the treatment of erlotinib-resistant NSCLC.

%I Frontiers