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ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases
- Source :
- Cancer research (Chic. Ill.) 62 (2002): 7284–7290., info:cnr-pdr/source/autori:Carlomagno F. 1, Vitagliano D. 1, Guida T. 1, Ciardiello F. 2, Tortora G. 2, Fontanini G. 3, Vecchio G. 1, Ryan A. 4, Fusco A. 1, Santoro M. 1/titolo:ZD6474, an Orally Available Inhibitor of KDR Tyrosine Kinase Activity, Efficiently Blocks Oncogenic RET Kinases./doi:/rivista:Cancer research (Chic. Ill.)/anno:2002/pagina_da:7284/pagina_a:7290/intervallo_pagine:7284–7290/volume:62, Scopus-Elsevier, Europe PubMed Central
- Publication Year :
- 2002
-
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.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
endocrine system
endocrine system diseases
Mice, Nude
ZD6474
Mice
Piperidines
KDR
Proto-Oncogene Proteins
Animals
Drosophila Proteins
TKI
RET
Thyroid Neoplasms
Enzyme Inhibitors
Phosphorylation
neoplasms
Mice, Inbred BALB C
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases
3T3 Cells
Vascular Endothelial Growth Factor Receptor-2
Carcinoma, Papillary
Cell Transformation, Neoplastic
Quinazolines
Signal Transduction
Subjects
Details
- ISSN :
- 00085472
- Volume :
- 62
- Issue :
- 24
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.pmid.dedup....24c6e8286301f2fb4608fb81f99f9252