title: Molecular imaging of active mutant L858R EGF receptor (EGFR) kinase-expressing nonsmall cell lung carcinomas using PET/CT.
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).
authors.affiliation: Department of Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, TX 77584, USA.
authors.forename: Hsin Hsien
authors.initials: HH
authors.lastname: Yeh
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Julius
authors.initials: J
authors.lastname: Balatoni
authors.forename: Uday
authors.initials: U
authors.lastname: Mukhapadhyay
authors.forename: Asutosh
authors.initials: A
authors.lastname: Pal
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez-Lepera
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Shavrin
authors.forename: Suren
authors.initials: S
authors.lastname: Soghomonyan
authors.forename: Leo
authors.initials: L
authors.lastname: Flores
authors.forename: Daniel
authors.initials: D
authors.lastname: Young
authors.forename: Andrei Y
authors.initials: AY
authors.lastname: Volgin
authors.forename: Amer M
authors.initials: AM
authors.lastname: Najjar
authors.forename: Victor
authors.initials: V
authors.lastname: Krasnykh
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism; D014057:Tomography, X-Ray Computed / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: C557742:4-((3-iodophenyl)amino)-7-(2-(2-(2-(2-(2-(2-(18F)fluoroethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)quinazoline-6-yl-acrylamide; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D066246:ErbB Receptors