Sunaga Noriaki, Miura Yosuke, Tsukagoshi Yusuke, Kasahara Norimitsu, Masuda Tomomi, Sakurai Reiko, Kaira Kyoichi, Hisada Takeshi
Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Innovative Medical Research Center, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.
Oncol Lett. 2019 Mar;17(3):3569-3575. doi: 10.3892/ol.2019.10009. Epub 2019 Feb 4.
Despite the high frequency of mutations in non-small cell lung cancer (NSCLC), therapeutic modalities targeting -mutated NSCLC have not been established. Based on our previous findings that mutant knockdown sensitized NSCLC cells to a p38 inhibitor, the growth-inhibitory effect of dual MEK and p38 inhibition on tumor growth in NSCLC cells harboring mutations was investigated. In -mutated NSCLC cells, the MEK inhibitor, selumetinib, inhibited cell growth in a dose-dependent manner, and its growth-inhibitory effect was enhanced by combined treatment with the p38 inhibitor LY2228820. Similarly, another pair of MEK and p38 inhibitors also exhibited antitumor activity. Small interfering RNAs (siRNAs) against , which encodes p38α MAPK, enhanced the growth-inhibitory effect of the MEK inhibitors in NSCLC cells with mutations. Notably, MEK inhibitors reduced p38 expression levels but increased p38 phosphorylation levels, resulting in sensitization to p38 inhibitors in -mutated NSCLC cells. These results provide evidence that dual MEK and p38 inhibition could be a potent therapeutic strategy against oncogenic -driven NSCLC.
尽管非小细胞肺癌（NSCLC）中突变频率很高，但针对突变型NSCLC的治疗方式尚未确立。基于我们之前的发现，即敲低突变体可使NSCLC细胞对p38抑制剂敏感，我们研究了双重抑制MEK和p38对携带突变的NSCLC细胞肿瘤生长的抑制作用。在突变型NSCLC细胞中，MEK抑制剂司美替尼以剂量依赖的方式抑制细胞生长，并且与p38抑制剂LY2228820联合治疗可增强其生长抑制作用。同样，另一对MEK和p38抑制剂也表现出抗肿瘤活性。针对编码p38α MAPK的的小干扰RNA（siRNA）增强了MEK抑制剂对携带突变的NSCLC细胞的生长抑制作用。值得注意的是，MEK抑制剂降低了p38表达水平，但增加了p38磷酸化水平，从而导致突变型NSCLC细胞对p38抑制剂敏感。这些结果证明，双重抑制MEK和p38可能是针对致癌驱动的NSCLC的有效治疗策略。
