TY - JOUR
T1 - Immuno-PET detects changes in multi-RTK tumor cell expression levels in response to targeted kinase inhibition
AU - Pereira, Patricia M.R.
AU - Norfleet, Jalen
AU - Lewis, Jason S.
AU - Escorcia, Freddy E.
N1 - Funding Information:
Onartuzumab was provided by Genentech. The Radiochemistry and Molecular Imaging Probe Core and the Antitumor Assessment Core were supported by NIH grant P30 CA08748. This study was supported in part by the Geoffrey Beene Cancer Research Center of MSKCC (Jason Lewis), NIH NCI grant R35 CA232130 (Jason Lewis), NIH NCI grant ZIA BC 011800 (Freddy Escorcia), Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center. Freddy Escorcia is supported by the American Board of Radiology Leonard B. Holman Research Pathway and the Clinical Investigator Development Program of NCI and NIH. Patricia Pereira is supported by the Tow Foundation Postdoctoral Fellowship from the MSKCC Center for Molecular Imaging and Nanotechnology and the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of MSKCC. No other potential conflict of interest relevant to this article was reported.
Publisher Copyright:
COPYRIGHT © 2021 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
KW - Immuno-PET
KW - Kinases
KW - Molecular imaging
KW - Oncology
KW - Theranostics
UR - http://www.scopus.com/inward/record.url?scp=85102219382&partnerID=8YFLogxK
U2 - 10.2967/jnumed.120.244897
DO - 10.2967/jnumed.120.244897
M3 - Article
C2 - 32646879
AN - SCOPUS:85102219382
SN - 0161-5505
VL - 62
SP - 366
EP - 371
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 3
ER -