Chiba Masato, Togashi Yosuke, Tomida Shuta, Mizuuchi Hiroshi, Nakamura Yu, Banno Eri, Hayashi Hidetoshi, Terashima Masato, De Velasco Marco A, Sakai Kazuko, Fujita Yoshihiko, Mitsudomi Tetsuya, Nishio Kazuto
Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
Department of Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
Int J Oncol. 2016 Dec;49(6):2236-2244. doi: 10.3892/ijo.2016.3736. Epub 2016 Oct 17.
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.
包括表皮生长因子受体（EGFR）、间变性淋巴瘤激酶（ALK）和间质上皮转化因子（MET）在内的几种受体酪氨酸激酶（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，丝裂原活化蛋白激酶（MAPK）通路对癌细胞的增殖、分化和存活尤为重要。在本研究中，使用MTT法在体外测试了MEK抑制剂（曲美替尼和PD0325901）对几种具有驱动基因改变，尤其是RTK基因改变的NSCLC细胞系的影响，结果发现敏感性差异很大。具体而言，所有EGFR突变的细胞系对MEK抑制剂均耐药，而所有MET扩增的细胞系均敏感。生物信息学技术和蛋白质免疫印迹分析表明，PI3K/AKT通路在EGFR突变的NSCLC中比在MET扩增的NSCLC中更活跃，并且PI3K抑制剂增强了EGFR突变细胞系对曲美替尼的敏感性，这表明该通路与对MEK抑制剂的耐药性有关。尽管HCC827细胞系（EGFR突变）对MEK抑制剂耐药，但驱动基因从EGFR转变为MET的HCC827CNXR细胞系对MEK抑制剂的敏感性增强，这表明MAPK通路对MET扩增的非小细胞肺癌具有生物学重要性。此外，在MET扩增的非小细胞肺癌细胞系中观察到克唑替尼（一种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MET扩增的NSCLC具有生物学重要性，并强烈鼓励开发针对MET扩增的NSCLC的MET抑制剂和MEK抑制剂联合疗法。
