Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells. Issue 1 (1st August 2015)

• Record Type: Journal Article
• Authors: Yao, Weilong; Yue, Ping; Zhang, Guojing; Owonikoko, Taofeek K.; Khuri, Fadlo R.; Sun, Shi-Yong
• Is Part Of: Cancer letters. Volume 364:Issue 1(2015)
• Page Start: 70
• Page End: 78
• Publication Date: 2015-08-01
• Subjects: MEK162 -- BKM120 -- Autophagy -- Lung cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.04.028
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: MEK162 inhibits the growth of human lung cancer cells with varied potencies. MEK162 induces G1 arrest, autophagy and/or apoptosis. MEK162 activates Akt signaling while effectively suppressing the MEK/ERK signaling. Blocking autophagy enhances MEK162's growth-inhibitory effects. The combination of MEK162 and BKM120, a PI3K inhibitor, significantly augments anticancer efficacy both in vitro and in vivo . Abstract: 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.