Monitoring Reversal of MET-Mediated Resistance to EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Using 3 '-Deoxy-3 '-[F-18]-Fluorothymidine Positron Emission Tomography
Keywords: Met Mediated Resistance, Egfr, Tyrosine Kinase, Inhibitors, Non Small Cell, Lung, Cancer, Fluorothymidine, Animals
, Antineoplastic Agents Pharmacology
, Blotting, Western
, Carcinoma, Non-Small-Cell Lung Radionuclide Imaging
, Cell Line, Tumor
, Drug Resistance, Neoplasm Genetics
, Female
, Fluorine Radioisotopes Diagnostic Use
, Humans
, Lung Neoplasms Radionuclide Imaging
, Mice
, Inbred Balb C
, Nude
, Positron-Emission Tomography Methods
, Protein Kinase Inhibitors Pharmacology
, Proto-Oncogene Proteins C-Met Genetics
, Pyrazoles Pharmacology
, Pyridines Pharmacology
, Quinazolines Pharmacology
, Rna Interference
, Radiopharmaceuticals Diagnostic Use
, Receptor, Epidermal Growth Factor Antagonists, Xenograft Model Antitumor Assays, Crizotinib, Epidermal Growth Factor Receptor, Erlotinib, Met Protein, Pyrazole Derivative, Pyridine Derivative, Quinazoline Derivative, Radiopharmaceutical Agent, Scatter Factor Receptor, Antagonists And Inhibitors, Bagg Albino Mouse, Drug Screening, Lung Tumor, Non Small Cell Lung Cancer, Nude Mouse, Positron Emission Tomography, Procedures, Scintiscanning, Tumor Cell Line, Western Blotting, Non-Small-Cell Lung Diagnostic Imaging
, Erlotinib Hydrochloride
, Lung Neoplasms Diagnostic Imaging,
Affiliations: *** IBB - CNR ***
Institute of Biostructures and Bioimages, National Research CouncilNaples, Italy
CEINGE-Advanced BiotechnologiesNaples, Italy
Department of Advanced Biomedical Sciences, University Federico II, Via Pansini 5, Edificio 10Napoli, Italy
References: Not available.
Monitoring Reversal of MET-Mediated Resistance to EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Using 3 '-Deoxy-3 '-[F-18]-Fluorothymidine Positron Emission Tomography
Purpose: 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'-[F-18]-fluorothymidine ([F-18]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. Experimental Design: 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 [F-18]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 [F-18]FLT uptake of 28% and 41% after low-and high-dose treatment with crizotinib for 3 days, whereas no posttherapy changes of [F-18]FLT uptake were observed in HCC827 tumors lacking MET amplification. Furthermore, a persistently high [F-18]FLT uptake was observed in H1993 tumors after treatment with erlotinib, whereas HCC827 tumors showed up to 39% reduction of [F-18]FLT uptake following erlotinib treatment. Imaging findings were confirmed by Ki67 immunostaining of tumor sections. Conclusions: [F-18]FLT PET/CT can detect MET-mediated resistance to EGFR TKIs and its reversal by MET inhibitors in NSCLC. (C)2014 AACR.
Monitoring Reversal of MET-Mediated Resistance to EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Using 3 '-Deoxy-3 '-[F-18]-Fluorothymidine Positron Emission Tomography
Monitoring Reversal of MET-Mediated Resistance to EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Using 3 '-Deoxy-3 '-[F-18]-Fluorothymidine Positron Emission Tomography
Kim YH, Shin SW, Pellicano R, Fagoonee S, Choi IJ, Kim YI, Park B, Choi JM, Kim SG, Choi J, Park JY, Oh S, Yang HJ, Lim JH, Im JP, Kim JS, Jung HC, Ponzetto A, Figura N, Malfertheiner P, Choi IJ, Kook MC, Kim YI, Cho SJ, Lee JY, Kim CG, Park B, Nam BH, Bae SE, Choi KD, Choe J, Kim SO, Na HK, Choi JY, Ahn JY, Jung KW, Lee J, Kim DH, Chang HS, Song HJ, Lee GH, Jung HY, Seta T, Takahashi Y, Noguchi Y, Shikata S, Sakai T, Sakai K, Yamashita Y, Nakayama T, Leja M, Park JY, Murillo R, Liepniece-karele I, Isajevs S, Kikuste I, Rudzite D, Krike P, Parshutin S, Polaka I, Kirsners A, Santare D, Folkmanis V, Daugule I, Plummer M, Herrero R, Tsukamoto T, Nakagawa M, Kiriyama Y, Toyoda T, Cao X, Corral JE, Mera R, Dye CW, Morgan DR, Lee YC, Lin JT, Garcia Martin R, Matia Cubillo A, Lee SH, Park JM, Han YM, Ko WJ, Hahm KB, Leontiadis GI, Ford AC, Ichinose M, Sugano K, Jeong M, Park JM, Han YM, Park KY, Lee DH, Yoo JH, Cho JY, Hahm KB, Bang CS, Baik GH, Shin IS, Kim JB, Suk KT, Yoon JH, Kim YS, Kim DJ * Helicobacter pylori Eradication for Prevention of Metachronous Recurrence after Endoscopic Resection of Early Gastric Cancer(565 views) N Engl J Med (ISSN: 0028-4793, 0028-4793linking, 1533-4406electronic), 2015 Jun; 30642104201566393291: 749-756. Impact Factor:59.558 ViewExport to BibTeXExport to EndNote