SRC and MEK Co-inhibition Synergistically Enhances the Anti-tumor Effect in Both Non-small-cell Lung Cancer (NSCLC) and Erlotinib-Resistant NSCLC

Frontiers in Oncology

Hongxi Xu¹  Hua Zhou¹  Yuan-zhi Lao²  Juan Zhang²  Si-yuan Kong²  Man Yuan²  Man Wu²  Li Zhang²  Lin-feng Xu³ 

[1] Institute of Cardiovascular Disease of Integrated Traditional Chinese Medicine and Western Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China;School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China;Shanghai Chempartner Co., Ltd, Shanghai, China;

关键词: non-small-cell lung cancer;    MEK and SRC inhibitor;    trametinib;    bosutinib;    synergistic effect;   

DOI  :  10.3389/fonc.2019.00586

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown