Targeting BRAFV600E in thyroid carcinoma: therapeutic implications
| Autor: | Vassiliki Poulaki, Galinos Fanourakis, Ciaran J. McMullan, Joseph Negri, Nicholas Mitsiades, Douglas W. McMillin, Gerassimos Voutsinas, Constantine S. Mitsiades, David Bryant Batt, Sophia Tseleni-Balafouta, Elias Sozopoulos |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Proto-Oncogene Proteins B-raf MAPK/ERK pathway Cancer Research Apoptosis Biology Thyroid carcinoma Adenocarcinoma Follicular Tumor Cells Cultured medicine Humans RNA Messenger Thyroid Neoplasms Anaplastic carcinoma Phosphorylation Extracellular Signal-Regulated MAP Kinases Thyroid cancer Aged Cell Proliferation Reverse Transcriptase Polymerase Chain Reaction Kinase Carcinoma Cancer Middle Aged Isoquinolines medicine.disease Carcinoma Papillary Oncology Mutation Cancer cell Carcinoma Squamous Cell Cancer research Female Mitogen-Activated Protein Kinases V600E Signal Transduction |
| Zdroj: | Molecular Cancer Therapeutics. 6:1070-1078 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-06-0449 |
| Popis: | 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 BRAFV600E specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAFV600E patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-RafV600E induced a comparable reduction of viability in both wild-type and BRAFV600E mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAFV600E-harboring cells than wild-type ones, possibly because of better inhibitory activity against B-RafV600E. We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-RafV600E may provide clinical benefit for patients with thyroid cancer. [Mol Cancer Ther 2007;6(3):1070–8] |
| Databáze: | OpenAIRE |
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