BRAF is a therapeutic target in aggressive thyroid carcinoma

Giuliana Salvatore, Valentina De Falco, Paolo Salerno, Tito Claudio Nappi, Stefano Pepe, Giancarlo Troncone, Francesca Carlomagno, Rosa Marina Melillo, Scott M. Wilhelm, Massimo Santoro

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1623-1629
Number of pages7
JournalClinical Cancer Research
Volume12
Issue number5
DOIs
Publication statusPublished - Mar 1 2006

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Salvatore, G., De Falco, V., Salerno, P., Nappi, T. C., Pepe, S., Troncone, G., Carlomagno, F., Melillo, R. M., Wilhelm, S. M., & Santoro, M. (2006). BRAF is a therapeutic target in aggressive thyroid carcinoma. Clinical Cancer Research, 12(5), 1623-1629. https://doi.org/10.1158/1078-0432.CCR-05-2378