title: MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations.
abstract: BACKGROUND
  Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation.
  
  
  METHODS
  The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts.
  
  
  RESULTS
  Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib.
  
  
  CONCLUSIONS
  Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tanizaki
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Kunio
authors.initials: K
authors.lastname: Okamoto
authors.forename: Ken
authors.initials: K
authors.lastname: Takezawa
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kuwata
authors.forename: Haruka
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D005784:Gene Amplification; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D000077022:Survivin; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met