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.
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Authors | Constantine S Mitsiades, Joseph Negri, Ciaran McMullan, Douglas W McMillin, Elias Sozopoulos, Galinos Fanourakis, Gerassimos Voutsinas, Sophia Tseleni-Balafouta, Vassiliki Poulaki, David Batt, Nicholas Mitsiades |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 6
Issue 3
Pg. 1070-8
(Mar 2007)
ISSN: 1535-7163 [Print] United States |
PMID | 17363500
(Publication Type: Journal Article)
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Chemical References |
- AAL 881
- Isoquinolines
- RNA, Messenger
- BRAF protein, human
- Proto-Oncogene Proteins B-raf
- Extracellular Signal-Regulated MAP Kinases
- Mitogen-Activated Protein Kinases
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Topics |
- Adenocarcinoma, Follicular
(genetics, pathology, prevention & control)
- Adult
- Aged
- Apoptosis
(drug effects)
- Carcinoma
(genetics, pathology, prevention & control)
- Carcinoma, Papillary
(genetics, pathology, prevention & control)
- Carcinoma, Squamous Cell
(genetics, pathology, prevention & control)
- Cell Proliferation
(drug effects)
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Female
- Humans
- Isoquinolines
(pharmacology)
- Male
- Middle Aged
- Mitogen-Activated Protein Kinases
(metabolism)
- Mutation
(genetics)
- Phosphorylation
(drug effects)
- Proto-Oncogene Proteins B-raf
(genetics)
- RNA, Messenger
(genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
(drug effects)
- Thyroid Neoplasms
(genetics, pathology, prevention & control)
- Tumor Cells, Cultured
(drug effects)
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