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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.

Original publication

DOI

10.1677/ERC-09-0292

Type

Journal article

Journal

Endocr Relat Cancer

Publication Date

02/2011

Volume

18

Pages

1 - 11

Keywords

Carcinoma, Medullary, Cell Line, Tumor, Cell Proliferation, ErbB Receptors, Humans, Mutation, Piperidines, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-ret, Quinazolines, Signal Transduction, Thyroid Neoplasms, Transforming Growth Factor alpha, Vascular Endothelial Growth Factor Receptor-2