MEK inhibitors against MET-amplified non-small cell lung cancer.
MEK inhibitors against MET-amplified non-small cell lung cancer.
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MEK 抑制剂针对 MET 扩增的非小细胞肺癌。
DOI：
10.3892/ijo.2016.3736
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发表时间：
2016-12
影响因子：
5.2
通讯作者：
Nishio K
中科院分区：
文献类型：
--
作者：
Chiba M;Togashi Y;Tomida S;Mizuuchi H;Nakamura Y;Banno E;Hayashi H;Terashima M;De Velasco MA;Sakai K;Fujita Y;Mitsudomi T;Nishio K
包括 EGFR、ALK 和 MET 在内的多种受体酪氨酸激酶 (RTK) 已被确定为非小细胞肺癌 (NSCLC) 的治疗靶点。在RTK的下游通路中，MAPK通路对于癌细胞的增殖、分化和存活尤为重要。在本研究中，使用 MTT 测定在体外测试了 MEK 抑制剂（曲美替尼和 PD0325901）在几种具有驱动基因改变（尤其是 RTK 基因）的 NSCLC 细胞系中的作用，并发现了广泛的敏感性。特别是，所有 EGFR 突变细胞系均对 MEK 抑制剂具有抗性，而所有 MET 扩增细胞系均敏感。生物信息学技术和蛋白质印迹分析表明，PI3K/AKT 通路在 EGFR 突变的 NSCLC 中比 MET 扩增的 NSCLC 中更加激活，并且 PI3K 抑制剂增强了 EGFR 突变的细胞系对曲美替尼 (Trametinib) 的敏感性，表明该通路与 MEK 抑制剂的耐药性相关。尽管HCC827细胞系（EGFR突变）对MEK抑制剂具有耐药性，但驱动基因从EGFR转变为MET的HCC827CNXR细胞系表现出对MEK抑制剂增强的敏感性，表明MAPK途径对于MET扩增的NCSLC的生物学重要性。此外，在 MET 扩增的 NCLC 细胞系中观察到克唑替尼（MET 抑制剂）和曲美替尼的协同作用。我们的研究结果表明，MAPK 通路对于 MET 扩增的 NSCLC 具有重要的生物学意义，并强烈鼓励开发 MET 抑制剂和 MEK 抑制剂针对 MET 扩增的 NSCLC 的联合疗法。
Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
影响因子：
20.4
作者：
Onozato, Ryoichi;Kosaka, Takayuki;Mitsudomi, Tetsuya
通讯作者：
Mitsudomi, Tetsuya
影响因子：
5.7
作者：
Mizuuchi, Hiroshi;Suda, Kenichi;Mitsudomi, Tetsuya
通讯作者：
Mitsudomi, Tetsuya
影响因子：
158.5
作者：
Mok, Tony S.;Wu, Yi-Long;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro