Abstract
BackgroundThyroid cancer is the most common endocrine-related cancer in the United States and its incidence is rising rapidly. Since among various genetic lesions identified in thyroid cancer, the BRAFV600E mutation is found in 50% of papillary thyroid cancers and 25% of anaplastic thyroid cancers, this mutation provides an opportunity for targeted drug therapy. Our laboratory evaluated cellular phenotypic effects in response to treatment with PLX4032, a BRAFV600E-specific inhibitor, in normal BRAF-wild-type thyroid cells and in BRAFV600E-positive papillary thyroid cancer cells.MethodsNormal BRAF-wild-type thyroid cells and BRAFV600E-mutated papillary thyroid cancer cells were subjected to proliferation assays and analyzed for cell death by immunofluorescence. Cell cycle status was determined using an EdU uptake assay followed by laser scanning cytometry. In addition, expression of proteins within the MAPK signal transduction pathway was analyzed by Western blot.ResultsPLX4032 has potent anti-proliferative effects selectively in BRAF-mutated thyroid cancer cells. These effects appear to be mediated by the drug’s activity of inhibiting phosphorylation of signaling molecules downstream of BRAF within the pro-survival MAPK pathway. Interestingly, PLX4032 promotes the phosphorylation of these signaling molecules in BRAF-wild-type thyroid cells.ConclusionsThese findings support further evaluation of combinational therapy that includes BRAFV600E inhibitors in thyroid cancer patients harboring the BRAFV600E mutation.
Highlights
Thyroid cancer is the most common endocrine-related cancer in the United States and its incidence is rising rapidly
We explore how inhibition of BRAFV600E leads to phenotypic changes in thyroid cells and demonstrate the selectivity of PLX4032-mediated inhibition in thyroid cells
The study is limited to one papillary thyroid cancer cell line and is not representative of all thyroid cancer cell lines harboring the BRAFV600E mutation, we present findings which characterize the interaction between a commonly mutated signal transduction molecule and a specific inhibitor
Summary
Thyroid cancer is the most common endocrine-related cancer in the United States and its incidence is rising rapidly. Our laboratory evaluated cellular phenotypic effects in response to treatment with PLX4032, a BRAFV600E-specific inhibitor, in normal BRAF-wild-type thyroid cells and in BRAFV600E-positive papillary thyroid cancer cells. Thyroid cancer is the most common endocrine-related cancer in the United States. Thyroid cancer can be classified as papillary, follicular, medullary or anaplastic. Papillary thyroid cancer (PTC) accounts for over 80% of all thyroid carcinoma. Most of the thyroid cancers are believed to originate in single cells due to mutations that confer growth advantages including increased proliferation, impaired apoptosis, enhanced angiogenesis, invasion and metastasis.
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