89Zr-Onartuzumab PET imaging of c-MET receptor dynamics.

Abstract

PURPOSE:

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 of 89Zr-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 underwent 89Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent 89Zr-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.

CONCLUSION:

The results show that 89Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.

• Authors: Martin Pool, Anton G T Terwisscha van Scheltinga, Arjan Kol, Danique Giesen, Elisabeth G E de Vries, Marjolijn N Lub-de Hooge
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 44 Issue 8 Pg. 1328-1336 (Aug 2017) ISSN: 1619-7089 [Electronic] Germany
• PMID: 28315949 (Publication Type: Journal Article)

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antibodies, Monoclonal
• HSP90 Heat-Shock Proteins
• Isoxazoles
• Radioisotopes
• Resorcinols
• Zirconium
• Erlotinib Hydrochloride
• MET protein, human
• Proto-Oncogene Proteins c-met
• onartuzumab
• Zirconium-89

Topics

• Animals
• Antibodies, Monoclonal
• Carcinoma, Non-Small-Cell Lung (diagnostic imaging, drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Drug Resistance, Neoplasm (drug effects)
• Erlotinib Hydrochloride (pharmacology, therapeutic use)
• Feasibility Studies
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (pharmacology, therapeutic use)
• Lung Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Male
• Mice
• Positron-Emission Tomography
• Proto-Oncogene Proteins c-met (metabolism)
• Radioisotopes
• Resorcinols (pharmacology, therapeutic use)
• Up-Regulation (drug effects)
• Zirconium