title: Crizotinib overcomes hepatocyte growth factor-mediated resistance to gefitinib in EGFR-mutant non-small-cell lung cancer cells.
abstract: Acquired 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.
authors: Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors: Xi
authors: X
authors: Chen
authors: Jian-Ya
authors: JY
authors: Zhou
authors: Jing
authors: J
authors: Zhao
authors: Jun-Jun
authors: JJ
authors: Chen
authors: Shan-Ni
authors: SN
authors: Ma
authors: Jian-Ying
authors: JY
authors: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib