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Research Articles: Therapeutics, Targets, and Development

Targeting BRAF^V600E in thyroid carcinoma: therapeutic implications

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, ² Department of Medicine, Harvard Medical School, and ³ Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; ⁴ Department of Pathology, University of Athens, ⁵ Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, National Center of Scientific Research "Demokritos", Athens, Greece; and ⁶ Oncology Research, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts

Requests for reprints: Constantine S. Mitsiades, Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer Building, Room M555, 44 Binney Street, Boston MA 02115. Phone: 617-792-7240; Fax: 617-812-7701. E-mail: Constantine_Mitsiades{at}dfci.harvard.edu

Abstract

B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We also compared the effect of a B-Raf small inhibitory RNA construct and the B-Raf kinase inhibitor AAL881 on both B-Raf wild-type and mutant thyroid carcinoma cell lines. We found a high prevalence of the T1799A (V600E) mutation in papillary and anaplastic carcinoma specimens and cell lines. There was no difference in patient age, B-Raf expression, Ki67 immunostaining, or clinical stage at presentation between wild-type and BRAF^V600E specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAF^V600E patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-Raf^V600E induced a comparable reduction of viability in both wild-type and BRAF^V600E mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAF^V600E-harboring cells than wild-type ones, possibly because of better inhibitory activity against B-Raf^V600E. We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-Raf^V600E may provide clinical benefit for patients with thyroid cancer. [Mol Cancer Ther 2007;6(3):1070–8]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/31/06; revised 10/29/06; accepted 1/22/07.

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