• Xi Chen, Jian-Ya Zhou, Jing Zhao, Jun-Jun Chen, Shan-Ni Ma, and Jian-Ying Zhou.
• Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
• Anticancer Drugs. 2013 Nov 1; 24 (10): 1039-46.

AbstractAcquired resistance develops ultimately in most non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations who initially respond to EGFR tyrosine kinase inhibitors. Overexpression of hepatocyte growth factor (HGF) contributes to a considerable part of acquired resistance. Therefore, novel approaches are required for better management to overcome the resistance. Here, we tested whether crizotinib (PF02341066), a MET kinase inhibitor, can overcome two different HGF-triggered mechanisms of resistance to gefitinib in human EGFR mutant lung cancer cell lines HCC827 and PC-9. Compared with the monotherapy, the combined treatment of crizotinib and gefitinib induced apoptosis and significantly inhibited the growth of cells in the presence of HGF by blocking the MET/PI3K/Akt pathway. Further, we demonstrated that crizotinib plus gefitinib successfully prevented the emergence of gefitinib-resistant HCC827 cells induced by transient exposure to HGF. In vivo, the combination therapy with crizotinib and gefitinib also markedly suppressed the growth of gefitinib-resistant mouse xenografts established by injecting HCC827 cells mixed with HGF-producing fibroblasts (MRC-5 cells) subcutaneously into severe combined immunodeficient mice. In conclusion, these findings provided preclinical evidence that crizotinib can be used in the treatment of HGF-induced resistance to gefitinib in EGFR mutant lung cancer.

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