Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells.
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.
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.
Weilong
W
Yao
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Ping
P
Yue
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Guojing
G
Zhang
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Taofeek K
TK
Owonikoko
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Fadlo R
FR
Khuri
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. Electronic address: ssun@emory.edu.
Shi-Yong
SY
Sun
D001343:Autophagy / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D001562:Benzimidazoles; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C581313:binimetinib
Autophagy; BKM120; Lung cancer; MEK162