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BRAF is a therapeutic target in aggressive thyroid carcinoma
- Source :
- Clinical cancer research, 12 (2006): 1623–1629., info:cnr-pdr/source/autori:Salvatore G, De Falco V, Salerno P, Nappi TC, Pepe S, Troncone G, Carlomagno F, Melillo RM, Wilhelm SM, Santoro M./titolo:BRAF is a therapeutic target in aggressive thyroid carcinoma./doi:/rivista:Clinical cancer research (Print)/anno:2006/pagina_da:1623/pagina_a:1629/intervallo_pagine:1623–1629/volume:12
- Publication Year :
- 2006
-
Abstract
- Purpose: Oncogenic conversion of BRAF occurs in ∼44% of papillary thyroid carcinomas and 24% of anaplastic thyroid carcinomas. In papillary thyroid carcinomas, this mutation is associated with an unfavorable clinicopathologic outcome. Our aim was to exploit BRAF as a potential therapeutic target for thyroid carcinoma. Experimental Design: We used RNA interference to evaluate the effect of BRAF knockdown in the human anaplastic thyroid carcinoma cell lines FRO and ARO carrying the BRAF V600E (V600EBRAF) mutation. We also exploited the effect of BAY 43-9006 [N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl pyridin-4-yl)oxyphenyl)urea], a multikinase inhibitor able to inhibit RAF family kinases in a panel of six V600EBRAF-positive thyroid carcinoma cell lines and in nude mice bearing ARO cell xenografts. Statistical tests were two sided. Results: Knockdown of BRAF by small inhibitory duplex RNA, but not control small inhibitory duplex RNA, inhibited the mitogen-activated protein kinase signaling cascade and the growth of ARO and FRO cells (P < 0.0001). These effects were mimicked by thyroid carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 μmol/L; P < 0.0001), whereas the compound had negligible effects in normal thyrocytes. ARO cell tumor xenografts were significantly (P < 0.0001) smaller in nude mice treated with BAY 43-9006 than in control mice. This inhibition was associated with suppression of phospho–mitogen-activated protein kinase levels. Conclusions: BRAF provides signals crucial for proliferation of thyroid carcinoma cells spontaneously harboring the V600EBRAF mutation and, therefore, BRAF suppression might have therapeutic potential in V600EBRAF-positive thyroid cancer.
- Subjects :
- Sorafenib
Male
Niacinamide
Proto-Oncogene Proteins B-raf
Cancer Research
endocrine system diseases
Pyridines
Cell
Transplantation, Heterologous
Thyroid Gland
Mice, Nude
BRAF
Thyroid carcinoma
multikinase inhibitor BAY 43-9006
phospho-mitogen-activated protein kinase inhibition
Mice
RNA interference
medicine
Carcinoma
Animals
Humans
Thyroid Neoplasms
RNA, Small Interfering
neoplasms
Thyroid cancer
cell growth inhibition
Cell Proliferation
Gene knockdown
Mice, Inbred BALB C
business.industry
Phenylurea Compounds
Benzenesulfonates
medicine.disease
digestive system diseases
Carcinoma, Papillary
Transplantation
medicine.anatomical_structure
Oncology
Mutation
Cancer research
Mitogen-Activated Protein Kinases
business
anaplastic thyroid carcinoma cell line
V600E
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 10780432
- Volume :
- 12
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....6b184bb580bf61641dce2234d995162a