Metformin sensitizes lung cancer cells to treatment by the tyrosine kinase inhibitor erlotinib

// Xiaofei Wang 1, 2,* , Keqiang Chen 2, *, Ying Yu 2, 3, Yi Xiang 1, Jae Hong Kim 2, Wanghua Gong 4, Jiaqiang Huang 5, Guochao Shi 1, Qingyun Li 1, Min Zhou 1, Thomas Sayers 4, Poonam Tewary 4, Beili Gao 1 and Ji Ming Wang 2 1 Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China 2 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA 3 Eye Institute, Affiliated Hospital of Nantong University, Nantong 226001, China 4 Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA 5 College of Life Sciences and Bioengineering, School of Sciences, Beijing Jiaoton University, Beijing 100044, China * These authors have contributed equally to this work Correspondence to: Ji Ming Wang, email: wangji@mail.nih.gov Beili Gao, email: yshu7661@sina.com Keywords: lung cancer; metformin; EGFR; erlotinib; phosphorylation Received: July 14, 2017      Accepted: August 21, 2017      Published: November 21, 2017 ABSTRACT Lung cancer is one of the deadliest malignant tumors with limited treatment options. Although targeted therapy, using tyrosine-kinase inhibitors such as erlotinib (Erlo), has shown therapeutic benefit, only 15 % patients with mutated epidermal growth factor receptor (EGFR) in lung cancer cells are sensitive. Therefore, additional therapeutic strategy should be developed. In this study, we found that metformin (Met), which is widely used for the treatment of type 2 diabetes (T2D), sensitized lung cancer cells bearing wild-type EGFR to Erlo treatment by enriching cancer cells expressing higher levels of EGFR with persistent phosphorylation. As a consequence, combination of Met and Erlo more efficiently inhibited the growth of lung cancer cells both in vitro and in mice with xenografted tumors. Our results suggest a novel approach to treating lung cancer cases which are originally resistant to Erlo.