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Parole chiave: 18f-Fdg Uptake, T790m Mediated Resistance, Met Amplification, Nsclc,
*** IBB - CNR *** Institute of Biostructures and Bioimages, National Research Council Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy
Aim: The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. We previously showed that 18F-FLT uptake is a reliable imaging biomarker of tumor response in refractory NSCLC due to both mechanisms of resistance. Here we tested whether 18F-FDG PET/CT is able to detect the T790M- or MET-mediated resistance and to monitor the reversal of such resistance by EGFR T790M or MET inhibitors in tumor-bearing animals.Materials and Methods: Erlotinib-resistant NSCLC cell lines (H1975 and H1993) were treated with WZ4002, an EGFR T790M inhibitor, or the MET-inhibitor crizotinib depending on the mechanism of resistance. The levels and phosphorylation status of key proteins in the glycolytic cascade and oxidative phosphorylation were tested in response to treatment along with 18F-FDG uptake. Then nude mice bearing H1975 and H1993 xenografts were subjected to 18F-FDG PET/CT scan before and after treatment (50 mg/kg p.o. for 3 days) with erlotinib, WZ4002, crizotinib or vehicle. Three-dimensional region of interest analysis was performed to determine the percent change of 18F-FDG uptake in response to treatment. At the end of imaging studies, tumors were removed, counted and analysed for glycolytic and mitochondrial proteins as well as signaling mediators. Results: H1975 cells showed a statistically significant reduction of 18F-FDG uptake in response to treatment with WZ4002 (-61% ± 10%, p=0.02) whereas tracer uptake remained unchanged in response to erlotinib. H1993 cells, despite their known MET-mediated resistance, showed a decrease of 18F-FDG uptake in response to erlotinib that became even stronger after treatment with the MET inhibitor (-70% ± 11%, p=0.04). Western blot analysis of glycolytic and mitochondrial proteins confirmed the different metabolic response of resistant H1975 and H1993 cells to erlotinib.In agreement with in vitro findings, imaging studies with 18F-FDG PET/CT in H1975 tumor-bearing mice showed a strong reduction of 18F-FDG uptake after treatment with WZ4002 whereas an increase of 18F-FDG uptake was observed after treatment with erlotinib. Conversely, H1993 tumors bearing MET amplification showed a reduction of 18F-FDG uptake after treatment with both crizotinib and erlotinib. The reduction of in vivo 18F-FDG uptake was always associated with downregulation of key glycolytic proteins and upregulation of mitochondrial complexes in excised tumors.Conclusion: 18F-FDG uptake is a reliable imaging biomarker of T790M-mediated resistance and its reversal in NSCLC whereas it fails to detect MET-mediated resistance.