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Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement

Cited 38 time in Web of Science Cited 46 time in Scopus
Authors
Henderson, Ying C.; Ahn, Soon-Hyun; Kang, Ya'an; Clayman, Gary L.
Issue Date
2008-08-05
Publisher
American Association for Cancer Research
Citation
Clin Cancer Res. 2008 ;14(15):4908-14.
Keywords
AnimalsAntineoplastic Agents/*pharmacologyBenzenesulfonates/*pharmacologyCarcinoma, Papillary/*drug therapy/metabolismCell Line, TumorCell ProliferationHumansMiceMice, Nude*MutationNeoplasm TransplantationProto-Oncogene Proteins B-raf/geneticsProto-Oncogene Proteins c-ret/*geneticsPyridines/*pharmacologySignal TransductionThyroid Neoplasms/*drug therapy/metabolism
Abstract
PURPOSE: Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignancy with one of the two mutations, RET/PTC rearrangement or BRAF mutation. Both mutations are able to activate the MEK/ERK signaling transduction pathway and result in the activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. Sorafenib (Nexavar, BAY 43-9006) is a multikinase inhibitor, and in this study, we tested its effects on PTC cells carrying either mutation. EXPERIMENTAL DESIGN: The effects of sorafenib on cell proliferation and signaling were evaluated in vitro on PTC cells using growth curves, cell cycle analysis, and immunoblotting. Using an orthotopic mouse model, we determined the antitumor effects of sorafenib in vivo. RESULTS: The concentration needed for 50% growth inhibition (GI(50)) by sorafenib was 0.14 mumol/L for the PTC cells with the RET/PTC1 rearrangement, and 2.5 mumol/L for PTC cells with a BRAF mutation, both readily achievable serum concentrations. After 3 weeks of oral administration of sorafenib (80 mg/kg/d) in mice, small (94% reduction compared with controls) or no tumor growth was detected in mice inoculated with PTC cells bearing the RET/PTC1 rearrangement, whereas the tumor volume of the orthotopic tumor implants of PTC cells with a BRAF mutation was reduced 53% to 54% (as compared with controls). CONCLUSIONS: PTC cells carrying the RET/PTC1 rearrangement were more sensitive to sorafenib than PTC cells carrying a BRAF mutation. Because RET/PTC rearrangements are unique to thyroid carcinomas, our findings support the clinical evaluation of sorafenib for patients with PTC and the identification of patients most likely to respond to sorafenib treatment.
ISSN
1078-0432 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18676765

https://hdl.handle.net/10371/63323
DOI
https://doi.org/10.1158/1078-0432.CCR-07-1772
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College of Medicine/School of Medicine (의과대학/대학원)Otorhinolaryngology (이비인후과학전공)Journal Papers (저널논문_이비인후과학전공)
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