title: Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer.
abstract: BACKGROUND
  Most clinically available small-molecule kinase inhibitors are multi-targeted and can inhibit multiple kinases. Our driving hypothesis was that one of these multi-targeted tyrosine kinase inhibitors (TKIs) would have antiproliferative activity against ROS1 translocated non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  We selected NSCLC cell lines--A549 (KRAS G12S), NCI-H3255 (EGFR L858R), NCI-H3122 (EML4-ALK E13;A20), and HCC78 (SLC34A2-ROS1)-to evaluate the antiproliferative effects of submicromolar concentrations of the multitargeted TKIs imatinib, sorafenib, erlotinib, and crizotinib.
  
  
  RESULTS
  Imatinib and sorafenib were unable to significantly inhibit proliferation of the aforementioned cell lines. Erlotinib only inhibited EGFR mutated NCI-H3255, as expected. Crizotinib displayed dose-dependent inhibition of anaplastic lymphoma kinase translocated NCI-H3122 and also ROS1--translocated HCC78. The SLC34A2-ROS1 translocated HCC78 cell line had phosphorylated levels of ROS1, AKT, and ERK inhibited by submicromolar doses of crizotinib, and subsequently underwent apoptosis.
  
  
  CONCLUSIONS
  The ROS1-translocated HCC78 cell line was sensitive to inhibition by the multitargeted ALK/MET/RON/ROS1 inhibitor crizotinib. Preclinical data supports the clinical development of crizotinib for ROS1-translocated NSCLC.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.forename: Lorena L
authors.initials: LL
authors.lastname: de Figueiredo-Pontes
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II