Document Detail


Sunitinib inhibits papillary thyroid carcinoma with RET/PTC rearrangement but not BRAF mutation.
MedLine Citation:
PMID:  21725210     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Sunitinib, a multi-targeted tyrosine kinase inhibitor, is frequently incorporated into the management of papillary thyroid carcinoma refractory to standard therapies. Although clinical trials are in progress, the mechanism of action in papillary thyroid carcinomas is not clear, especially regarding the effect on BRAF mutation. We investigated the effect of sunitinib on papillary thyroid carcinoma cells harboring RET/PTC rearrangement and BRAF mutation using TPC-1M, SNU-790, and B-cPAP cell lines. Cell growth of papillary thyroid cancer cells with RET/PTC rearrangement was effectively inhibited at low doses of sunitinib (IC50=0.658 μM), whereas that of BRAF mutated cells required higher doses. Immunoblotting revealed effective blocking of MEK/ERK pathway in RET/PTC rearrangement cells, but not in BRAF mutated cells. Cell cycle analysis showed G1 arrest in RET/PTC rearrangement cells. In vivo orthotopic thyroid cancer mouse model demonstrated statistically significant tumor growth inhibition by sunitinib in RET/PTC rearrangement cancer cells. We conclude that sunitinib effectively inhibits RET/PTC rearrangement cells but not BRAF mutated cells. These data suggest that sunitinib exerts its effect by inhibiting the upstream MAPK signaling cascade. These findings support the unsatisfactory treatment outcomes of sunitinib in many already ongoing clinical trials compared to other tyrosine kinase inhibitors. Clinical application of sunitinib should be directed accordingly.
Authors:
Woo-Jin Jeong; Ji-Hun Mo; Min Woo Park; Ik Joon Choi; Soo-Youn An; Eun-Hee Jeon; Soon-Hyun Ahn
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-09-01
Journal Detail:
Title:  Cancer biology & therapy     Volume:  12     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-02     Completed Date:  2012-01-26     Revised Date:  2012-06-21    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  458-65     Citation Subset:  IM    
Affiliation:
Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
DNA-Binding Proteins / genetics*
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Humans
Indoles / pharmacology*
MAP Kinase Kinase Kinases / antagonists & inhibitors
Mice
Mutation
Nuclear Proteins / genetics*
Proto-Oncogene Proteins B-raf / genetics*
Pyrroles / pharmacology*
Signal Transduction / drug effects
Thyroid Neoplasms / drug therapy*,  genetics,  prevention & control*
Xenograft Model Antitumor Assays
raf Kinases / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Indoles; 0/Nuclear Proteins; 0/Pyrroles; 0/TRIM27 protein, human; 0/sunitinib; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 2.7.11.1/raf Kinases; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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