Abstract
AimDespite 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.ResultsThe 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 designThe 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.ConclusionsMetformin may be used in combination with crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong survival.
Highlights
Genomic alterations in the anaplastic lymphoma kinase (ALK) gene are found in numerous malignancies [1]
Metformin may be used in combination with crizotinib in ALK+ non-small cell lung cancer (NSCLC) patients to overcome crizotinib resistance and prolong survival
The expression of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion oncogene, which is caused by a small inversion within chromosome 2p, was found in non-small cell lung cancer (NSCLC) [2]
Summary
Genomic alterations in the anaplastic lymphoma kinase (ALK) gene are found in numerous malignancies [1]. ALK rearrangements, first discovered by Soda et al in 2007 [2], are either inversions or translocations of the ALK-tyrosine kinase (-TK) receptor gene with other fusion partners. The product of the ALK rearrangement consists of a constitutively activated receptor TK with pro-oncogenic effects [3]. Crizotinib is a multitargeted TKI with activity against MET, ALK, and ROS1 [4, 5]. This active substance has been found to greatly outperform the best chemotherapy agents in NSCLC patients with ALK rearrangements [6, 7]. The other mechanism is activation of alternative signaling pathways, including the development of EGFR mutations or activation of the wild-type EGFR, HER2-, or KIT-
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