1. Molecular imaging of active mutant L858R EGF receptor (EGFR) kinase-expressing nonsmall cell lung carcinomas using PET/CT.
- Author
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Yeh HH, Ogawa K, Balatoni J, Mukhapadhyay U, Pal A, Gonzalez-Lepera C, Shavrin A, Soghomonyan S, Flores L 2nd, Young D, Volgin AY, Najjar AM, Krasnykh V, Tong W, Alauddin MM, and Gelovani JG
- Subjects
- Amino Acid Substitution, Animals, Binding, Competitive, Blotting, Western, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation drug effects, ErbB Receptors genetics, Fluorodeoxyglucose F18 metabolism, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Mice, Mice, Nude, Mutant Proteins genetics, Mutation, Positron-Emission Tomography methods, Protein Binding, Protein Kinase Inhibitors pharmacology, Quinazolines metabolism, Radiopharmaceuticals metabolism, Tomography, X-Ray Computed methods, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung metabolism, ErbB Receptors metabolism, Lung Neoplasms metabolism, Molecular Imaging methods, Mutant Proteins metabolism
- Abstract
The importance of the EGF receptor (EGFR) signaling pathway in the development and progression of nonsmall cell lung carcinomas (NSCLC) is widely recognized. Gene sequencing studies revealed that a majority of tumors responding to EGFR kinase inhibitors harbor activating mutations in the EGFR kinase domain. This underscores the need for novel biomarkers and diagnostic imaging approaches to identify patients who may benefit from particular therapeutic agents and approaches with improved efficacy and safety profiles. To this goal, we developed 4-[(3-iodophenyl)amino]-7-{2-[2-{2-(2-[2-{2-([(18)F]fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide ([(18)F]F-PEG6-IPQA), a radiotracer with increased selectivity and irreversible binding to the active mutant L858R EGFR kinase. We show that PET with [(18)F]F-PEG6-IPQA in tumor-bearing mice discriminates H3255 NSCLC xenografts expressing L858R mutant EGFR from H441 and PC14 xenografts expressing EGFR or H1975 xenografts with L858R/T790M dual mutation in EGFR kinase domain, which confers resistance to EGFR inhibitors (i.e., gefitinib). The T790M mutation precludes the [(18)F]F-PEG6-IPQA from irreversible binding to EGFR. These results suggest that PET with [(18)F]F-PEG6-IPQA could be used for the selection of NSCLC patients for individualized therapy with small molecular inhibitors of EGFR kinase that are currently used in the clinic and have a similar structure (i.e., iressa, gefitinib, and erlotinib).
- Published
- 2011
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