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The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells
- Source :
- Endocrine-related cancer 18 (2011): 1–11. doi:10.1677/ERC-09-0292, info:cnr-pdr/source/autori:Vitagliano, Donata; De Falco, Valentina; Tamburrino, Anna; Coluzzi, Sabrina; Troncone, Giancarlo; Chiappetta, Gennaro; Ciardiello, Fortunato; Tortora, Giampaolo; Fagin, James A.; Ryan, Anderson J.; Carlomagno, Francesca; Santoro, Massimo/titolo:The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells/doi:10.1677%2FERC-09-0292/rivista:Endocrine-related cancer/anno:2011/pagina_da:1/pagina_a:11/intervallo_pagine:1–11/volume:18, info:cnr-pdr/source/autori:Vitagliano D, De Falco V, Tamburrino A, Coluzzi S, Troncone G, Chiappetta G, Ciardiello F, Tortora G, Fagin JA, Ryan AJ, Carlomagno F, Santoro M./titolo:The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells./doi:10.1677%2FERC-09-0292/rivista:Endocrine-related cancer/anno:2011/pagina_da:1/pagina_a:11/intervallo_pagine:1–11/volume:18
- Publication Year :
- 2011
- Publisher :
- BioScientifica, Bristol , Regno Unito, 2011.
-
Abstract
- Oncogenic conversion of the RET tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). ZD6474 (vandetanib) is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, we have studied ZD6474 mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively. ZD6474 blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the ZD6474-resistant V804M RET mutant rescued proliferation of TT cells under ZD6474 treatment, showing that RET is a key ZD6474 target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by ZD6474 may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR.
- Subjects :
- MAPK/ERK pathway
Cancer Research
congenital, hereditary, and neonatal diseases and abnormalities
endocrine system
endocrine system diseases
medicine.drug_class
Endocrinology, Diabetes and Metabolism
Vandetanib
Tyrosine-kinase inhibitor
Endocrinology
Piperidines
Cell Line, Tumor
tyrosine kinase inhibitors
medicine
thyroid cancer
Humans
Thyroid Neoplasms
Epidermal growth factor receptor
Protein kinase A
Protein Kinase Inhibitors
neoplasms
Cell Proliferation
ret
medullary thyroid carcinoma
tyrosine kinase inhibitor
biology
Kinase
Cell growth
Proto-Oncogene Proteins c-ret
tyrosine kinase
Transforming Growth Factor alpha
targeted therapy
Vascular Endothelial Growth Factor Receptor-2
ErbB Receptors
Oncology
Carcinoma, Medullary
Mutation
Quinazolines
Cancer research
biology.protein
cancer therapy
Tyrosine kinase
carcinoma midollare della tiroide
Signal Transduction
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Endocrine-related cancer 18 (2011): 1–11. doi:10.1677/ERC-09-0292, info:cnr-pdr/source/autori:Vitagliano, Donata; De Falco, Valentina; Tamburrino, Anna; Coluzzi, Sabrina; Troncone, Giancarlo; Chiappetta, Gennaro; Ciardiello, Fortunato; Tortora, Giampaolo; Fagin, James A.; Ryan, Anderson J.; Carlomagno, Francesca; Santoro, Massimo/titolo:The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells/doi:10.1677%2FERC-09-0292/rivista:Endocrine-related cancer/anno:2011/pagina_da:1/pagina_a:11/intervallo_pagine:1–11/volume:18, info:cnr-pdr/source/autori:Vitagliano D, De Falco V, Tamburrino A, Coluzzi S, Troncone G, Chiappetta G, Ciardiello F, Tortora G, Fagin JA, Ryan AJ, Carlomagno F, Santoro M./titolo:The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells./doi:10.1677%2FERC-09-0292/rivista:Endocrine-related cancer/anno:2011/pagina_da:1/pagina_a:11/intervallo_pagine:1–11/volume:18
- Accession number :
- edsair.doi.dedup.....d1ad36104319b36c3628874b80f31228