title: ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases.
abstract: RET/papillary thyroid carcinoma (PTC) oncogenes, generated by recombination of the tyrosine kinase-encoding domain of RET with different heterologous genes, are prevalent in papillary carcinomas of the thyroid. Point mutations of RET cause multiple endocrine neoplasia type 2 (MEN2) familial cancer syndrome and are found in sporadic medullary thyroid carcinomas. Here, we show that ZD6474, a low molecular weight tyrosine kinase inhibitor, blocks the enzymatic activity of RET-derived oncoproteins at a one-half maximal inhibitory concentration of 100 nM. ZD6474 blocked in vivo phosphorylation and signaling of the RET/PTC3 and RET/MEN2B oncoproteins and of an epidermal growth factor (EGF)-activated EGF-receptor/RET chimeric receptor. RET/PTC3-transformed cells-treated ZD6474 lost proliferative autonomy and showed morphological reversion. ZD6474 prevented the growth of two human PTC cell lines that carry spontaneous RET/PTC1 rearrangements. Finally, it blocked anchorage-independent growth of RET/PTC3-transformed NIH3T3 fibroblasts and the formation of tumors after injection of NIH-RET/PTC3 cells into nude mice. Thus, targeting RET oncogenes with ZD6474 might offer a potential treatment strategy for carcinomas sustaining oncogenic activation of RET.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare Luigi Califano, University Federico II, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
authors.forename: Donata
authors.initials: D
authors.lastname: Vitagliano
authors.forename: Teresa
authors.initials: T
authors.lastname: Guida
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Vecchio
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret; D011799:Quinazolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib