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Inositol Trisphosphate Receptor Type 3-mediated Enhancement of EGFR and MET Cotargeting Efficacy in Non-Small Cell Lung Cancer Detected by (18)F-fluorothymidine (260 visite)
Clin Cancer Res (ISSN: 1078-0432print, 1078-0432linking), 2018 Jul 1; 24(13): 3126-3136.
Tipo di articolo: Journal Article,
Impact factor: 10.199
Impact factor a 5 anni: 6.646
Parole chiave: Non disponibili.
Url: Non disponibile.
Purpose: Our aim was to test whether imaging with (18)F-fluorothymidine ((18)F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small cell lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination.Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent (18)F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and posttreatment changes of (18)F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA.Results: Imaging studies showed a significant reduction of (18)F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F-ratio = 6.215, P = 0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib, whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras.Conclusions: Our findings indicate that (18)F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras. Clin Cancer Res; 24(13); 3126-36. (c)2018 AACR.
*** IBB - CNR ***
Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy., CEINGE-Advanced Biotechnologies, Naples Italy., Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy., Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy. firstname.lastname@example.org.,
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