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

Francesca Iommelli, Viviana De Rosa, Sara Gargiulo, Mariarosaria Panico, Marcello Monti, Adelaide Greco, Matteo Gramanzini, Giovanni Ortosecco, Rosa Fonti, Arturo Brunetti, Silvana Del Vecchio

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Abstract

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′-[18F]-fluorothymidine ([18F]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 [18F]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 bearingMETamplification showed a mean reduction in [18F]FLT uptake of28% and 41% after low- and high-dose treatment with crizotinib for 3 days, whereas no posttherapy changes of [18F]FLT uptake were observed in HCC827 tumors lacking MET amplification. Furthermore, a persistently high [18F]FLT uptake was observed in H1993 tumors after treatment with erlotinib, whereas HCC827 tumors showed up to 39% reduction of [18F]FLT uptake following erlotinib treatment. Imaging findings were confirmed by Ki67 immunostaining of tumor sections.

Conclusions: [18F]FLT PET/CT can detect MET-mediated resistance to EGFR TKIs and its reversal by MET inhibitors in NSCLC.

Original languageEnglish
Pages (from-to)4806-4815
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number18
DOIs
Publication statusPublished - Sep 15 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Iommelli, F., De Rosa, V., Gargiulo, S., Panico, M., Monti, M., Greco, A., Gramanzini, M., Ortosecco, G., Fonti, R., Brunetti, A., & Del Vecchio, S. (2014). 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. Clinical Cancer Research, 20(18), 4806-4815. https://doi.org/10.1158/1078-0432.CCR-14-0264