The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells Journal Article
| Authors: | Vitagliano, D.; De Falco, V.; Tamburrino, A.; Coluzzi, S.; Troncone, G.; Chiappetta, G.; Ciardiello, F.; Tortora, G.; Fagin, J. A.; Ryan, A. J.; Carlomagno, F.; Santoro, M. |
| Article Title: | The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells |
| 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. © 2011 Society for Endocrinology. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; human cell; mutation; cell cycle; gene expression; amino acid substitution; protein targeting; epidermal growth factor receptor; rna interference; antineoplastic activity; cancer cell culture; cancer inhibition; enzyme phosphorylation; nucleotide sequence; vandetanib; mitogen activated protein kinase 1; mitogen activated protein kinase 3; threonine; gene silencing; protein ret; carcinoma cell; methionine; cysteine; tryptophan; thyroid medullary carcinoma; protein shc |
| Journal Title: | Endocrine-Related Cancer |
| Volume: | 18 |
| Issue: | 1 |
| ISSN: | 1351-0088 |
| Publisher: | Bioscientifica Ltd |
| Date Published: | 2011-02-01 |
| Start Page: | 1 |
| End Page: | 11 |
| Language: | English |
| DOI: | 10.1677/erc-09-0292 |
| PROVIDER: | scopus |
| PUBMED: | 20943719 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 March 2011" - "CODEN: ERCAE" - "Source: Scopus" |
