title: Monitoring reversal of MET-mediated resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer using 3'-deoxy-3'-[18F]-fluorothymidine positron emission tomography.
abstract: OBJECTIVE
  MET amplification is one of the mechanisms underlying acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Here, we tested whether 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]FLT) positron emission tomography/computerized tomography (PET/CT) can detect MET-mediated resistance to EGFR TKIs and monitor the effects of MET inhibitors in NSCLC.
  
  
  METHODS
  H1993 and H820 NSCLC cells with high and low levels of MET amplification, respectively, and HCC827-expressing MET, but without gene amplification, were tested for the effects of MET inhibitors on the EGFR pathway and proliferation both in vitro and in vivo. Nude mice bearing NSCLCs with and without MET amplification were subjected to [(18)F]FLT PET/CT before and after treatment with crizotinib or erlotinib (50 mg/kg and 100 mg/kg p.o. for 3 days).
  
  
  RESULTS
  H1993 cells showed high responsiveness to MET inhibitors and were resistant to erlotinib. Conversely, HCC827 cells showed high sensitivity to erlotinib and were resistant to MET inhibitors. Accordingly, H1993 tumors bearing MET amplification showed a mean reduction in [(18)F]FLT uptake of 28% and 41% after low- and high-dose treatment with crizotinib for 3 days, whereas no posttherapy changes of [(18)F]FLT uptake were observed in HCC827 tumors lacking MET amplification. Furthermore, a persistently high [(18)F]FLT uptake was observed in H1993 tumors after treatment with erlotinib, whereas HCC827 tumors showed up to 39% reduction of [(18)F]FLT uptake following erlotinib treatment. Imaging findings were confirmed by Ki67 immunostaining of tumor sections.
  
  
  CONCLUSIONS
  [(18)F]FLT PET/CT can detect MET-mediated resistance to EGFR TKIs and its reversal by MET inhibitors in NSCLC.
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy.
authors: Francesca
authors: F
authors: Iommelli
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy.
authors: Viviana
authors: V
authors: De Rosa
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy. CEINGE-Advanced Biotechnologies, Naples Italy.
authors: Sara
authors: S
authors: Gargiulo
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy.
authors: Mariarosaria
authors: M
authors: Panico
authors: Department of Advanced Biomedical Sciences, University "Federico II," Naples, Italy.
authors: Marcello
authors: M
authors: Monti
authors: CEINGE-Advanced Biotechnologies, Naples Italy. Department of Advanced Biomedical Sciences, University "Federico II," Naples, Italy.
authors: Adelaide
authors: A
authors: Greco
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy. CEINGE-Advanced Biotechnologies, Naples Italy.
authors: Matteo
authors: M
authors: Gramanzini
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy.
authors: Giovanni
authors: G
authors: Ortosecco
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy.
authors: Rosa
authors: R
authors: Fonti
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy. CEINGE-Advanced Biotechnologies, Naples Italy. Department of Advanced Biomedical Sciences, University "Federico II," Naples, Italy.
authors: Arturo
authors: A
authors: Brunetti
authors: Institute of Biostructures and Bioimages, National Research Council, Naples, Italy. CEINGE-Advanced Biotechnologies, Naples Italy. Department of Advanced Biomedical Sciences, University "Federico II," Naples, Italy. delvecc@unina.it.
authors: Silvana
authors: S
authors: Del Vecchio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D019275:Radiopharmaceuticals; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005462:Fluorine Radioisotopes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D019275:Radiopharmaceuticals; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met