Yao Weilong, Yue Ping, Zhang Guojing, Owonikoko Taofeek K, Khuri Fadlo R, Sun Shi-Yong
Department of Respiration, Xiangya Hospital and Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Cancer Lett. 2015 Aug 1;364(1):70-8. doi: 10.1016/j.canlet.2015.04.028. Epub 2015 Apr 29.
Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due to a high frequency of K-Ras mutation and is thus a potential candidate for MEK-targeted therapy. The current study focuses on demonstrating the activity of MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis. Moreover, it induces autophagy and accordingly the combination of MEK162 with the autophagy inhibitor, chloroquine, synergistically inhibits the growth of NSCLC cells and enhances apoptosis. MEK162 activates Akt signaling while effectively inhibiting MEK/ERK signaling. Accordingly, the combination of MEK162 and BKM120 (buparlisib), a pan-PI3K inhibitor, abrogates induced Akt activation and significantly augments therapeutic efficacy against the growth of NSCLC cells both in vitro and in vivo. Hence our findings warrant further evaluation of these rational combinations in the clinic.
人类非小细胞肺癌（NSCLC）由于K-Ras突变频率高而表现出MEK/ERK信号通路激活，因此是MEK靶向治疗的潜在候选对象。当前研究聚焦于证明处于临床试验阶段的MEK抑制剂MEK162（比美替尼）对NSCLC的活性，并探索可能的机制驱动策略以提高其治疗效果。MEK162通过诱导G1期细胞周期阻滞和凋亡，以不同效力抑制人NSCLC细胞系的生长。此外，它还诱导自噬，因此MEK162与自噬抑制剂氯喹联合使用可协同抑制NSCLC细胞的生长并增强凋亡。MEK162在有效抑制MEK/ERK信号通路的同时激活Akt信号通路。因此，MEK162与泛PI3K抑制剂BKM120（布帕利西布）联合使用可消除诱导的Akt激活，并在体外和体内均显著增强对NSCLC细胞生长的治疗效果。因此，我们的研究结果值得在临床上对这些合理组合进行进一步评估。
