18F-FLT PET/CT for Detection of Functional Cross-talk between MET and EGFR in Non-small Cell Lung Cancer Resistant to EGFR Inhibitors (Abstract in rivista)

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  • 18F-FLT PET/CT for Detection of Functional Cross-talk between MET and EGFR in Non-small Cell Lung Cancer Resistant to EGFR Inhibitors (Abstract in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Alternative label
  • F. Iommelli, V. De Rosa, S. Gargiulo, M. Panico, M. Monti, G. Ortosecco, A. Greco, M. Gramanzini, R. Fonti, A. Brunetti, S. Del Vecchio (2013)
    18F-FLT PET/CT for Detection of Functional Cross-talk between MET and EGFR in Non-small Cell Lung Cancer Resistant to EGFR Inhibitors
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • F. Iommelli, V. De Rosa, S. Gargiulo, M. Panico, M. Monti, G. Ortosecco, A. Greco, M. Gramanzini, R. Fonti, A. Brunetti, S. Del Vecchio (literal)
Rivista
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  • -Institute of Biostructures and Bioimages, National Research Council, Naples, Italy; -Department of Advanced Biomedical Sciences, University \"Federico II\", Naples, Italy (literal)
Titolo
  • 18F-FLT PET/CT for Detection of Functional Cross-talk between MET and EGFR in Non-small Cell Lung Cancer Resistant to EGFR Inhibitors (literal)
Abstract
  • Targeting epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the most promising treatment strategies in patients with advanced non-small cell lung cancer (NSCLC). Despite the initial response, most tumors may become resistant to EGFR TKIs for different molecular mechanisms including MET amplification. A high copy number of MET is reported indeed to cause EGFR TKI resistance through HER3-dependent activation of EGFR signaling pathway. Here we tested whether 18F-FLT PET/CT is able to detect the functional cross-talk between MET and EGFR signaling pathways in NSCLC and to monitor the effects of treatment with MET inhibitors. Methods: NSCLC cell lines H1993 and H820 with a high and low level of MET amplification, respectively, and HCC827 expressing MET but without oncogene amplification were selected and tested for the effects of MET inhibitors on EGFR pathway and proliferation both in vitro and in vivo. The sensitivity of cells to MET inhibitors and EGFR TKIs was preliminarily tested and levels of total and phosphorylated forms of HER3, EGFR, MET, AKT and ERK1/2 as well as cyclin D1 were analyzed in untreated and treated cells. Nude mice bearing NSCLCs with and without MET amplification were injected with 7.4 MBq of 18F-FLT and subjected to PET/CT before and after treatment with MET inhibitor or EGFR TKI (50 mg/Kg p.o. for 3 days). Untreated and treated tumors were then removed and subjected to Ki67 immunostaining. Results: H1993 cells showed a high responsiveness to MET inhibitor and were resistant to EGFR TKIs. Conversely, HCC827 cells showed a high sensitivity to EGFR TKIs and were resistant to MET inhibitor. Accordingly, EGFR pathway was blocked by MET inhibitor in H1993 cells whereas it remained unchanged in HCC827 cells. In agreement with in vitro findings, a strong reduction of 18F-FLT uptake was observed in tumors bearing MET amplification in response to treatment with MET inhibitor whereas no post-therapy changes of 18F-FLT uptake was observed in lung tumors lacking MET amplification. Furthermore a persistently high 18F-FLT uptake was observed in tumors bearing MET amplification after treatment with EGFR TKIs. Imaging findings were confirmed by Ki67 immunostaining of tumor sections. Conclusion: 18F-FLT PET/CT is able to detect the functional cross-talk between MET and EGFR causing resistance to EGFR TKIs and to monitor the reversal of such resistance by MET inhibitors. (literal)
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