Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

// Li Li 1, * , Yubo Wang 1, * , Tao Peng 1, * , Kejun Zhang 2 , Caiyu Lin 1 , Rui Han 1 , Conghua Lu 1 , Yong He 1 1 Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China 2 Department of Clinical Labratory, Daping Hospital, Third Military Medical University, Chongqing 400042, China * These authors contributed equally to this work Correspondence to: Yong He, email: heyong@dphospital.tmmu.edu.cn Keywords: metformin, crizotinib, IGF-1R, lung cancer, resistance Received: November 01, 2015      Accepted: March 31, 2016      Published: April 30, 2016 ABSTRACT Aim: Despite the impressive efficacy of crizotinib for the treatment of ALK-positive non-small cell lung cancer, patients invariably develop therapeutic resistance. Suppression of the IGF-1R signaling pathway may abrogate this acquired mechanism of drug resistance to crizotinib. Metformin, a widely used antidiabetic agent, may reverse crizotinib resistance through inhibition of IGF-1R signaling. Results: The present study revealed that metformin effectively increased the sensitivity of both crizotinib-sensitive and -resistant non-small cell lung cancer cells to crizotinib, as evidenced by decreased proliferation and invasion and enhanced apoptosis. Metformin reduced IGF-1R signaling activation in crizotinib-resistant cells. Furthermore, the addition of IGF-1 to crizotinib-sensitive H2228 cells induced crizotinib resistance, which was overcome by metformin. Experimental design: The effects of metformin to reverse crizotinib resistance were examined in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), invasion assay, ki67 incorporation assay, flow cytometry analysis, Western blot analysis, and colony-forming assay. Conclusions: Metformin may be used in combination with crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong survival.