Aim: Two different molecular mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) were reported to occur in refractory non-small cell lung cancer (NSCLC) patients. About half of resistant tumors develop T790M secondary mutation in EGFR whereas MET amplification is found in 15-20% of refractory tumors. Therefore several targeted agents have been developed and tested to overcome T790M and MET-mediated resistance. However, a poor clinical response to treatment with EGFR TKIs is often the result of concurrent mechanisms of resistance and combination therapies might be essential for the improvement of the outcome in those patients. Here we tested the effect of combined treatment with EGFR and MET inhibitors in NSCLCs bearing MET amplification with or without T790M mutation of EGFR. 18F-FLT PET/CT was used to monitor in vivo drug effects and reversal of resistance. Methods: NSCLC H1993 cells with MET amplification and H820 cells with MET amplification and T790M mutation of EGFR were selected and tested for the effects of EGFR and MET inhibitors, alone or in combination, on downstream signaling mediators and proliferation. Untreated and treated cells were analyzed for levels of total and phosphorylated forms of EGFR, MET, HER3, AKT and ERK1/2 as well as cyclin D1. Nude mice bearing NSCLCs were injected with 7.4 MBq of 18F-FLT and subjected to PET/CT before and after treatment with EGFR and MET inhibitors alone or in combination. Results: In the selected NSCLC cell lines the combined treatment with EGFR and MET inhibitors caused the highest suppression of downstream signaling pathway and proliferation as compared to treatment with each inhibitor alone. In agreement with in vitro findings, NSCLC xenografts with concurrent mechanisms of resistance showed a stronger reduction of 18F-FLT uptake after combined treatment with EGFR and MET inhibitors as compared to treatment with single agent. Conclusion: Our findings indicate that 18F-FLT PET/CT may be used to guide and monitor combined treatment with EGFR and MET inhibitors in refractory NSCLC patients.
Monitoring Reversal of Concurrent Mechanisms of Resistance to EGFR TKIs in Non-Small Cell Lung Cancer by 18F-FLT PET/CT
F Iommelli;V De Rosa;S Gargiulo;M Panico;M Gramanzini;R Fonti;
2014
Abstract
Aim: Two different molecular mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) were reported to occur in refractory non-small cell lung cancer (NSCLC) patients. About half of resistant tumors develop T790M secondary mutation in EGFR whereas MET amplification is found in 15-20% of refractory tumors. Therefore several targeted agents have been developed and tested to overcome T790M and MET-mediated resistance. However, a poor clinical response to treatment with EGFR TKIs is often the result of concurrent mechanisms of resistance and combination therapies might be essential for the improvement of the outcome in those patients. Here we tested the effect of combined treatment with EGFR and MET inhibitors in NSCLCs bearing MET amplification with or without T790M mutation of EGFR. 18F-FLT PET/CT was used to monitor in vivo drug effects and reversal of resistance. Methods: NSCLC H1993 cells with MET amplification and H820 cells with MET amplification and T790M mutation of EGFR were selected and tested for the effects of EGFR and MET inhibitors, alone or in combination, on downstream signaling mediators and proliferation. Untreated and treated cells were analyzed for levels of total and phosphorylated forms of EGFR, MET, HER3, AKT and ERK1/2 as well as cyclin D1. Nude mice bearing NSCLCs were injected with 7.4 MBq of 18F-FLT and subjected to PET/CT before and after treatment with EGFR and MET inhibitors alone or in combination. Results: In the selected NSCLC cell lines the combined treatment with EGFR and MET inhibitors caused the highest suppression of downstream signaling pathway and proliferation as compared to treatment with each inhibitor alone. In agreement with in vitro findings, NSCLC xenografts with concurrent mechanisms of resistance showed a stronger reduction of 18F-FLT uptake after combined treatment with EGFR and MET inhibitors as compared to treatment with single agent. Conclusion: Our findings indicate that 18F-FLT PET/CT may be used to guide and monitor combined treatment with EGFR and MET inhibitors in refractory NSCLC patients.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
