(89)Zr-Onartuzumab PET imaging of c-MET receptor dynamicsPool, M., van Scheltinga, A. G. T. T., Kol, A., Giesen, D., de Vries, E. G. E. & Lub-de Hooge, M. N., Aug-2017, In : European Journal of Nuclear Medicine and Molecular Imaging. 44, 8, p. 1328-1336 9 p.
Research output: Contribution to journal › Article › Academic › peer-review
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 (89)Zr-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 (89)Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent (89)Zr-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, (89)Zr-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 (89)Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.
|Number of pages||9|
|Journal||European Journal of Nuclear Medicine and Molecular Imaging|
|Publication status||Published - Aug-2017|
- Onartuzumab, c-MET, HSP90, Zr-89, Erlotinib, PET, CELL LUNG-CANCER, HEPATOCYTE GROWTH-FACTOR, HSP90 INHIBITOR NVP-AUY922, BREAST-CANCER, ZR-89-BEVACIZUMAB PET, KINASE INHIBITORS, TUMOR XENOGRAFT, DOWN-REGULATION, IMMUNO-PET, PHASE-II