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Updated: Dec 15, 2025
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Immuno-PET Detects Changes in Multi-RTK Tumor Cell Expression Levels in Response to Targeted Kinase Inhibition
Patricia M R Pereira1, Jalen Norfleet1, Jason S Lewis1,2
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Receptor tyrosine kinase (RTK) coexpression facilitates tumor resistance due to redundancies in the phosphatidylinositol-3'-kinase/protein kinase B and KRAS/extracellular-signal-regulated kinase signaling pathways, among others. Crosstalk between the oncogenic RTK hepatocyte growth factor receptor (MET), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2) are involved in tumor resistance to RTK-targeted therapies. Methods: In a relevant renal cell carcinoma patient-derived xenograft model, we use the 89Zr-labeled anti-RTK antibodies (immuno-PET) onartuzumab, panitumumab, and trastuzumab to monitor MET, EGFR, and HER2 protein levels, respectively, during treatment with agents to which the model was resistant (cetuximab) or sensitive (INC280 and trametinib). Results: Cetuximab treatment resulted in continued tumor growth, as well as an increase in all RTK protein levels at the tumor in vivo on immuno-PET and ex vivo at the cellular level. Conversely, after dual MET/mitogen-activated protein kinase inhibition, tumor growth was significantly blunted and corresponded to a decrease in RTK levels. Conclusion: These data show the utility of RTK-targeted immuno-PET to annotate RTK changes in protein expression and inform tumor response to targeted therapies.
Insights
Receptor tyrosine kinase (RTK) coexpression drives tumor resistance. Immuno-PET imaging revealed that targeting RTK pathways can overcome resistance and decrease RTK levels, improving targeted therapy response.
Area of Science:
- Oncology
- Molecular Biology
- Radiochemistry
Background:
- Receptor tyrosine kinase (RTK) coexpression contributes to tumor resistance through redundant signaling pathways like PI3K/AKT and RAS/ERK.
- Crosstalk among MET, EGFR, and HER2 oncogenic RTKs promotes resistance to targeted therapies.
Purpose of the Study:
- To evaluate the utility of RTK-targeted immuno-PET for monitoring RTK expression during targeted therapy in a renal cell carcinoma model.
- To assess the impact of targeted therapy on RTK protein levels and tumor response.
Main Methods:
- Utilized 89Zr-labeled anti-RTK antibodies (onartuzumab, panitumumab, trastuzumab) for immuno-PET imaging in a renal cell carcinoma patient-derived xenograft model.
- Monitored MET, EGFR, and HER2 protein levels in vivo and ex vivo during treatment with cetuximab, INC280, and trametinib.
Main Results:
- Cetuximab treatment led to increased RTK levels and continued tumor growth.
- Dual MET/MAPK inhibition significantly blunted tumor growth and decreased RTK protein levels.
- Immuno-PET successfully annotated changes in RTK expression correlating with treatment response.
Conclusions:
- RTK-targeted immuno-PET is valuable for annotating dynamic changes in RTK protein expression.
- Immuno-PET can inform and guide tumor response to targeted therapies by visualizing RTK modulation.
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