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89Zr-Onartuzumab PET imaging of c-MET receptor dynamics
Martin Pool1, Anton G T Terwisscha van Scheltinga2, Arjan Kol1
1Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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.
Insights
This study shows that 89Zr-labeled onartuzumab PET can noninvasively detect changes in c-MET levels in non-small-cell lung cancer xenografts, aiding in monitoring treatment response.
Area of Science:
- Oncology
- Molecular Imaging
- Cancer Biology
Background:
- c-MET dysregulation is common in human cancers.
- Monitoring c-MET dynamics can guide targeted therapies and predict treatment outcomes.
- Noninvasive imaging of c-MET is crucial for personalized cancer treatment.
Purpose of the Study:
- To assess the feasibility of 89Zr-labeled onartuzumab PET for visualizing c-MET dynamics.
- To detect changes in c-MET levels induced by erlotinib resistance or HSP90 inhibition.
- To evaluate the potential of this imaging technique in non-small-cell lung cancer (NSCLC) xenografts.
Main Methods:
- Generated an erlotinib-resistant NSCLC cell line (HCC827ErlRes) with c-MET upregulation.
- Utilized 89Zr-onartuzumab PET imaging in mice bearing HCC827 and HCC827ErlRes xenografts.
- Correlated in vivo PET data with ex vivo c-MET immunohistochemistry.
Main Results:
- 89Zr-onartuzumab PET showed significantly higher uptake in erlotinib-resistant tumors.
- PET imaging detected a significant decrease in c-MET levels in tumors treated with NVP-AUY922.
- In vitro and in vivo results demonstrated the ability to track c-MET level alterations.
Conclusions:
- 89Zr-onartuzumab PET is effective in discriminating relevant changes in c-MET levels.
- This imaging approach holds potential for clinical monitoring of c-MET status in cancer patients.
- Noninvasive c-MET visualization can guide c-MET-directed therapies.
