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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Carcinoma, Papillary / genetics
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Carcinoma, Papillary / pathology
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Carcinoma, Papillary / prevention & control
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics
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Drosophila Proteins*
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Enzyme Inhibitors / pharmacology*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Phosphorylation / drug effects
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Piperidines / pharmacology*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-ret
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Quinazolines / pharmacology*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases / physiology
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Signal Transduction / drug effects
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / pathology
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Thyroid Neoplasms / prevention & control
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Substances
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Drosophila Proteins
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Enzyme Inhibitors
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Piperidines
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Proto-Oncogene Proteins
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Quinazolines
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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Ret protein, mouse
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Vascular Endothelial Growth Factor Receptor-2
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vandetanib