title: Quantitative analysis of [11C]-erlotinib PET demonstrates specific binding for activating mutations of the EGFR kinase domain.
abstract: Activating mutations of the epidermal growth factor receptor (EGFR) occur in multiple tumor types, including non-small cell lung cancer (NSCLC) and malignant glioma, and have become targets for therapeutic intervention. The determination of EGFR mutation status using a noninvasive, molecular imaging approach has the potential for clinical utility. In this study, we investigated [(11)C]-erlotinib positron emission tomography (PET) imaging as a tool to identify activating mutations of EGFR in both glioma and NSCLC xenografts. Radiotracer specific binding was determined for high and low specific activity (SA) [(11)C]-erlotinib PET scans in mice bearing synchronous human cancer xenografts with different EGFR expression profiles (PC9, HCC827, U87, U87 ΔEGFR, and SW620). Although xenograft immunohistochemistry demonstrated constitutive EGFR phosphorylation, PET scan analysis using the Simplified Reference Tissue Model showed that only kinase domain mutant NSCLC (HCC827 and PC9) had significantly greater binding potentials in high versus low SA scans. Xenografts with undetectable EGFR expression (SW620), possessing wild-type EGFR (U87), and expressing an activating extracellular domain mutation (U87 ΔEGFR) were indistinguishable under both high and low SA scan conditions. The results suggest that [(11)C]-erlotinib is a promising radiotracer that could provide a novel clinical methodology for assessing EGFR and erlotinib interactions in patients with tumors that harbor EGFR-activating kinase domain mutations.
authors.affiliation: Department of Diagnostic Radiology, Yale University, New Haven, CT ; Department of Biomedical Engineering, Yale University, New Haven, CT.
authors.forename: J Ryan
authors.initials: JR
authors.lastname: Petrulli
authors.affiliation: Department of Diagnostic Radiology, Yale University, New Haven, CT ; Department of Biomedical Engineering, Yale University, New Haven, CT.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: Department of Diagnostic Radiology, Yale University, New Haven, CT.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Department of Therapeutic Radiology, Yale University, New Haven, CT.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bennett
authors.affiliation: Department of Therapeutic Radiology, Yale University, New Haven, CT.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Charest
authors.affiliation: Department of Diagnostic Radiology, Yale University, New Haven, CT.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Diagnostic Radiology, Yale University, New Haven, CT ; Department of Biomedical Engineering, Yale University, New Haven, CT.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Morris
authors.affiliation: Department of Therapeutic Radiology, Yale University, New Haven, CT.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Contessa
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011799:Quinazolines; D019275:Radiopharmaceuticals
chemical_list: D002250:Carbon Radioisotopes; D011799:Quinazolines; D019275:Radiopharmaceuticals; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors