89Zr-Onartuzumab PET imaging of c-MET receptor dynamics.
OBJECTIVE
c-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of89Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts.


METHODS
In vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent89Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent89Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results.


RESULTS
In vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213 ± 44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69 ± 9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo,89Zr-onartuzumab uptake was 26% higher (P < 0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P < 0.001) following NVP-AUY-922 treatment.


CONCLUSIONS
The results show that89Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Martin
M
Pool
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
Anton G T
AGT
Terwisscha van Scheltinga
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Arjan
A
Kol
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Danique
D
Giesen
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Elisabeth G E
EGE
de Vries
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. m.n.de.hooge@umcg.nl.|Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. m.n.de.hooge@umcg.nl.
Marjolijn N
MN
Lub-de Hooge
D000818:Animals; D000911:Antibodies, Monoclonal; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D005240:Feasibility Studies; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011868:Radioisotopes; D012118:Resorcinols / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D015040:Zirconium
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000911:Antibodies, Monoclonal; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D011868:Radioisotopes; D012118:Resorcinols; D015040:Zirconium; D000069347:Erlotinib Hydrochloride; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab; C000615502:Zirconium-89
89Zr; Erlotinib; HSP90; Onartuzumab; PET; c-MET