Early 18F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors

Abstract

Background: The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. The aim of the present study was to test whether early changes of 18F-fluorodeoxyglucose (18F-FDG) uptake in animal models bearing erlotinib-resistant NSCLC may have different imaging patterns of response to erlotinib depending on the molecular mechanisms underlying resistance. Animal tumor models were developed using NSCLC H1975 cells bearing the T790M mutation and H1993 cells with MET amplification. Nude mice bearing erlotinib-resistant H1975 and H1993 xenografts (four animals for each cell line and for each treatment) were subjected to 18F-FDG PET/CT scan before and immediately after treatment (50 mg/kg p.o. for 3 days) with erlotinib, WZ4002, crizotinib, or vehicle. A 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 the imaging studies, tumors were removed and analyzed for glycolytic and mitochondrial proteins as well as levels of cyclin D1. Results: Imaging studies with 18F-FDG PET/CT in H1975 tumor-bearing mice showed a reduction of 18F-FDG uptake of 25.87 % ± 8.93 % after treatment with WZ4002 whereas an increase of 18F-FDG uptake up to 23.51 % ± 9.72 % was observed after treatment with erlotinib or vehicle. Conversely, H1993 tumors showed a reduction of 18F-FDG uptake after treatment with both crizotinib (14.70 % ± 1.30 %) and erlotinib (18.40 % ± 9.19 %) and an increase of tracer uptake in vehicle-treated (56.65 % ± 5.65 %) animals. The in vivo reduction of 18F-FDG uptake was always associated with downregulation of HKII and p-PKM2 Tyr105 glycolytic proteins and upregulation of mitochondrial complexes (subunits I–IV) in excised tumors. Conclusions: 18F-FDG uptake is a reliable imaging biomarker of T790M-mediated resistance and its reversal in NSCLC whereas it may not be accurate in the detection of MET-mediated resistance.