zd-6474 and Cell-Transformation--Neoplastic

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.

Topics: 3T3 Cells; Animals; Carcinoma, Papillary; Cell Transformation, Neoplastic; Drosophila Proteins; Enzyme Inhibitors; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Quinazolines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2