Alexander Traxl1, Taraneh Beikbaghban2, Thomas Wanek1, Kushtrim Kryeziu3, Christine Pirker2, Severin Mairinger1, Johann Stanek4, Thomas Filip1, Michael Sauberer1, Claudia Kuntner1, Walter Berger2, Oliver Langer5. 1. Biomedical Systems, Center for Health & Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria. 2. Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 3. Institute for Cancer Research, Department of Molecular Oncology, Oslo University Hospital HE - Norwegian Radium Hospital, Oslo, Norway. 4. Biomedical Systems, Center for Health & Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 5. Biomedical Systems, Center for Health & Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria. Electronic address: oliver.langer@ait.ac.at.
Abstract
INTRODUCTION: [11C]Erlotinib PET has shown promise to distinguish non-small cell lung cancer (NSCLC) tumors harboring the activating epidermal growth factor receptor (EGFR) mutation delE746-A750 from tumors with wild-type EGFR. To assess the suitability of [11C]erlotinib PET to detect the emergence of acquired erlotinib resistance in initially erlotinib-responsive tumors, we performed in vitro binding and PET experiments in mice bearing tumor xenografts using a range of different cancer cells, which were erlotinib-sensitive or exhibited clinically relevant resistance mechanisms to erlotinib. METHODS: The following cell lines were used for in vitro binding and PET experiments: the epidermoid carcinoma cell line A-431 (erlotinib-sensitive, wild-type EGFR) and the three NSCLC cell lines HCC827 (erlotinib-sensitive, delE746-A750), HCC827EPR (erlotinib-resistant, delE746-A750 and T790M) and HCC827ERLO (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [11C]erlotinib PET scans, a baseline scan and a second scan in which unlabeled erlotinib (10mg/kg) was co-injected. Logan graphical analysis was used to estimate total distribution volume (VT) of [11C]erlotinib in tumors. RESULTS: In vitro experiments revealed significantly higher uptake of [11C]erlotinib (5.2-fold) in the three NSCLC cell lines as compared to A-431 cells. In all four cell lines co-incubation with unlabeled erlotinib (1μM) led to significant reductions in [11C]erlotinib uptake (-19% to -66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral [11C]erlotinib VT values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral VT was significantly reduced following co-injection of unlabeled erlotinib (-20% to -35%). CONCLUSIONS: We found no significant differences in the in vitro and in vivo binding of [11C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [11C]erlotinib PET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib.
INTRODUCTION:[11C]ErlotinibPET has shown promise to distinguish non-small cell lung cancer (NSCLC) tumors harboring the activating epidermal growth factor receptor (EGFR) mutation delE746-A750 from tumors with wild-type EGFR. To assess the suitability of [11C]erlotinibPET to detect the emergence of acquired erlotinib resistance in initially erlotinib-responsive tumors, we performed in vitro binding and PET experiments in mice bearing tumor xenografts using a range of different cancer cells, which were erlotinib-sensitive or exhibited clinically relevant resistance mechanisms to erlotinib. METHODS: The following cell lines were used for in vitro binding and PET experiments: the epidermoid carcinoma cell line A-431 (erlotinib-sensitive, wild-type EGFR) and the three NSCLC cell lines HCC827 (erlotinib-sensitive, delE746-A750), HCC827EPR (erlotinib-resistant, delE746-A750 and T790M) and HCC827ERLO (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [11C]erlotinibPET scans, a baseline scan and a second scan in which unlabeled erlotinib (10mg/kg) was co-injected. Logan graphical analysis was used to estimate total distribution volume (VT) of [11C]erlotinib in tumors. RESULTS: In vitro experiments revealed significantly higher uptake of [11C]erlotinib (5.2-fold) in the three NSCLC cell lines as compared to A-431 cells. In all four cell lines co-incubation with unlabeled erlotinib (1μM) led to significant reductions in [11C]erlotinib uptake (-19% to -66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral[11C]erlotinib VT values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral VT was significantly reduced following co-injection of unlabeled erlotinib (-20% to -35%). CONCLUSIONS: We found no significant differences in the in vitro and in vivo binding of [11C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [11C]erlotinibPET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib.
Authors: Antonia Högnäsbacka; Alex J Poot; Danielle J Vugts; Guus A M S van Dongen; Albert D Windhorst Journal: Pharmaceuticals (Basel) Date: 2022-04-05