SRC and MEK Co-inhibition Synergistically Enhances the Anti-tumor Effect in Both Non-small-cell Lung Cancer (NSCLC) and Erlotinib-Resistant NSCLC
SRC and MEK Co-inhibition Synergistically Enhances the Anti-tumor Effect in Both Non-small-cell Lung Cancer (NSCLC) and Erlotinib-Resistant NSCLC
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SRC 和 MEK 共同抑制协同增强非小细胞肺癌 (NSCLC) 和厄洛替尼耐药 NSCLC 的抗肿瘤作用
DOI：
10.3389/fonc.2019.00586
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发表时间：
2019-07
影响因子：
4.7
通讯作者：
Xu Hongxi
中科院分区：
文献类型：
--
作者：
Yuan Man;Xu Lin feng;Zhang Juan;Kong Si yuan;Wu Man;Lao Yuan zhi;Zhou Hua;Zhang Li;Xu Hongxi
非小细胞肺癌（NSCLC）是肺癌的主要形式，其受复杂的信号转导网络调控。单药靶向治疗往往导致获得性耐药，从而导致治疗失败。在这项研究中，我们证明了激酶抑制剂曲美替尼和博舒替尼的组合可以通过抑制丝裂原活化蛋白激酶（MAPK）和原癌基因酪氨酸蛋白激酶（SRC）途径协同抑制NSCLC的生长。该组合针对一组22种NSCLC细胞系（包括一种厄洛替尼耐药细胞系）进行了分析，发现该组合对16种细胞系显示出协同作用。NSCLC细胞系（HCC 827、HCC 827-厄洛替尼耐药和H1650）用曲美替尼、博舒替尼或这些药物的组合治疗。药物组合抑制集落形成并诱导细胞凋亡。机制研究表明，NSCLC中表皮生长因子受体（EGFR）信号通路中多个激酶的磷酸化水平下调。此外，该组合以低毒性显著减弱HCC 827异种移植物的肿瘤生长。本研究结果为进一步研究MAPK和SRC通路抑制剂联合应用治疗NSCLC，尤其是治疗厄洛替尼耐药NSCLC提供了理论依据。
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.
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影响因子：
3.8
作者：
Tamarozzi F;Silva R;Fittipaldo VA;Buonfrate D;Gottstein B;Siles-Lucas M
通讯作者：
Siles-Lucas M
影响因子：
11.2
作者：
Gopal YN;Deng W;Woodman SE;Komurov K;Ram P;Smith PD;Davies MA
通讯作者：
Davies MA
影响因子：
4.7
作者：
Welch, Stephen;Hirte, Hal W.;Oza, Amit M.
通讯作者：
Oza, Amit M.
表皮生长因子受体和KRAS突变对以前未经治疗的非小细胞肺癌患者的临床结果的影响：临床试验的在线肿瘤注册表的结果。
DOI：
10.1158/1078-0432.ccr-09-0888
发表时间：
2009-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jackman DM;Miller VA;Cioffredi LA;Yeap BY;Jänne PA;Riely GJ;Ruiz MG;Giaccone G;Sequist LV;Johnson BE
通讯作者：
Johnson BE
DOI：
10.1891/9780826121646.0002
发表时间：
2018-09
期刊：
Cancer Rehabilitation
影响因子：
--
作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
通讯作者：
K. Miller;R. Siegel;R. Khan;A. Jemal