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%
Early 18F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in NSCLC
De Rosa V;Iommelli F;
2015
Abstract
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%I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
