Abstract | CONTEXT: The V600E mutation accounts for the vast majority of thyroid carcinoma-associated BRAF mutations. OBJECTIVE: EXPERIMENTAL DESIGN: We examined the activity of PLX4032 and PLX4720 in thyroid carcinoma cell lines harboring BRAF V600E (8505C, BCPAP, SW1736, BHT101), NRAS Q61R (HTH7), KRAS G12R (CAL62), HRAS G13R (C643), or RET/PTC1 (TPC-1) oncogenes. Normal thyrocytes (PC Cl 3) were used as control. RESULTS: Both compounds inhibited the proliferation of BRAF mutant cell lines, but not normal thyrocytes, with a half maximal effective concentration (EC(50)) ranging from 78-113 nm for PLX4720 and from 29-97 nm for PLX4032. Doses equal to or higher than 500 nm were required to achieve a similar effect in BRAF wild-type cancer cells. Phosphorylation of ERK 1/2 and MAPK kinase ( MEK) 1/2 decreased upon PLX4032 and PLX4720 treatment in BRAF mutant thyroid carcinoma cells but not in normal thyroid cells or in cell lines harboring mutations of RAS or RET/PTC1 rearrangements. PLX4032 and PLX4720 treatment induced a G(1) block and altered expression of genes involved in the control of G(1)-S cell-cycle transition. 8505C cell tumor xenografts were smaller in nude mice treated with PLX4032 than in control mice. This inhibition was associated with reduction of phospho-ERK and phospho- MEK levels. CONCLUSIONS: This study provides additional evidence of the promising nature of mutant BRAF as a molecular target for thyroid carcinoma cells.
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Authors | Paolo Salerno, Valentina De Falco, Anna Tamburrino, Tito Claudio Nappi, Giancarlo Vecchio, Rebecca E Schweppe, Gideon Bollag, Massimo Santoro, Giuliana Salvatore |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 95
Issue 1
Pg. 450-5
(Jan 2010)
ISSN: 1945-7197 [Electronic] United States |
PMID | 19880792
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cytostatic Agents
- Indoles
- Mutant Proteins
- PLX 4720
- Protein Kinase Inhibitors
- Sulfonamides
- Adenosine Triphosphate
- BRAF protein, human
- Proto-Oncogene Proteins B-raf
- Extracellular Signal-Regulated MAP Kinases
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Topics |
- Adenosine Triphosphate
(antagonists & inhibitors, metabolism)
- Binding, Competitive
(drug effects)
- Carcinoma
(genetics, pathology)
- Cell Proliferation
(drug effects)
- Cytostatic Agents
(pharmacology)
- Drug Evaluation, Preclinical
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Humans
- Indoles
(pharmacology)
- Mutant Proteins
(antagonists & inhibitors, genetics)
- Phosphorylation
(drug effects)
- Protein Kinase Inhibitors
(pharmacology)
- Proto-Oncogene Proteins B-raf
(antagonists & inhibitors, genetics)
- Serum
(physiology)
- Sulfonamides
(pharmacology)
- Thyroid Neoplasms
(genetics, pathology)
- Tumor Cells, Cultured
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