ImmunoPET Detects Changes in Multi-RTK Tumor Cell Expression Levels in Response to Targeted Kinase Inhibition.

Receptor tyrosine kinase (RTK) co-expression facilitates tumor resistance due to redundancies in the PI3K-AKT and KRAS-ERK signaling pathways, among others. Crosstalk between the oncogenic RTKs 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 (RCC) patient derived xenograft (PDX) model, we use zirconium-89 (89Zr)-labeled anti-RTKs antibodies (immunoPET) 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 immunoPET, and ex vivo at the cellular level. Conversely, following dual MET/MEK inhibition, tumor growth was significantly blunted, and corresponded with a decrease in RTK levels. Conclusion: These data show the utility of RTK-targeted immunoPET to annotate RTK changes in protein expression and inform tumor response to targeted therapies.