PMID- 20943719
OWN - NLM
STAT- MEDLINE
DCOM- 20110316
LR  - 20220325
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Linking)
VI  - 18
IP  - 1
DP  - 2011 Feb
TI  - The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary 
      thyroid carcinoma cells.
PG  - 1-11
LID - 10.1677/ERC-09-0292 [doi]
AB  - 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.
FAU - Vitagliano, Donata
AU  - Vitagliano D
AD  - Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita Federico 
      II, Napoli, Italy.
FAU - De Falco, Valentina
AU  - De Falco V
FAU - Tamburrino, Anna
AU  - Tamburrino A
FAU - Coluzzi, Sabrina
AU  - Coluzzi S
FAU - Troncone, Giancarlo
AU  - Troncone G
FAU - Chiappetta, Gennaro
AU  - Chiappetta G
FAU - Ciardiello, Fortunato
AU  - Ciardiello F
FAU - Tortora, Giampaolo
AU  - Tortora G
FAU - Fagin, James A
AU  - Fagin JA
FAU - Ryan, Anderson J
AU  - Ryan AJ
FAU - Carlomagno, Francesca
AU  - Carlomagno F
FAU - Santoro, Massimo
AU  - Santoro M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101130
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Piperidines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (Transforming Growth Factor alpha)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
RN  - EC 2.7.10.1 (RET protein, human)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
RN  - YO460OQ37K (vandetanib)
SB  - IM
MH  - Carcinoma, Medullary/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - ErbB Receptors/antagonists & inhibitors/physiology
MH  - Humans
MH  - Mutation
MH  - Piperidines/*pharmacology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-ret/*antagonists & inhibitors/genetics/physiology
MH  - Quinazolines/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Thyroid Neoplasms/*drug therapy/pathology
MH  - Transforming Growth Factor alpha/pharmacology
MH  - Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
EDAT- 2010/10/15 06:00
MHDA- 2011/03/17 06:00
CRDT- 2010/10/15 06:00
PHST- 2010/10/15 06:00 [entrez]
PHST- 2010/10/15 06:00 [pubmed]
PHST- 2011/03/17 06:00 [medline]
AID - ERC-09-0292 [pii]
AID - 10.1677/ERC-09-0292 [doi]
PST - epublish
SO  - Endocr Relat Cancer. 2010 Nov 30;18(1):1-11. doi: 10.1677/ERC-09-0292. Print 2011 
      Feb.