The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells

Endocr Relat Cancer. 2010 Nov 30;18(1):1-11. doi: 10.1677/ERC-09-0292. Print 2011 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Medullary / drug therapy*
  • Carcinoma, Medullary / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / physiology
  • Humans
  • Mutation
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / physiology
  • Quinazolines / pharmacology*
  • Signal Transduction / drug effects
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology
  • Transforming Growth Factor alpha / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

  • Piperidines
  • Protein Kinase Inhibitors
  • Quinazolines
  • Transforming Growth Factor alpha
  • ErbB Receptors
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • vandetanib