Disruption of mutated BRAF signaling modulates thyroid cancer phenotype.

Abstract

BACKGROUND:

Thyroid 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.

METHODS:

Normal 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.

RESULTS:

PLX4032 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.

CONCLUSIONS:

These findings support further evaluation of combinational therapy that includes BRAFV600E inhibitors in thyroid cancer patients harboring the BRAFV600E mutation.

• Authors: Elyse K Hanly, Shilpi Rajoria, Zbigniew Darzynkiewicz, Hong Zhao, Robert Suriano, Neha Tuli, Andrea L George, Robert Bednarczyk, Edward J Shin, Jan Geliebter, Raj K Tiwari
• Journal: BMC research notes (BMC Res Notes) Vol. 7 Pg. 187 (Mar 28 2014) ISSN: 1756-0500 [Electronic] England
• PMID: 24673746 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Sulfonamides
• Vemurafenib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma (drug therapy, genetics, metabolism, pathology)
• Carcinoma, Papillary
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Indoles (pharmacology)
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Mutation
• Phenotype
• Phosphorylation
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Thyroid Cancer, Papillary
• Thyroid Carcinoma, Anaplastic (drug therapy, genetics, metabolism, pathology)
• Thyroid Gland (drug effects, metabolism, pathology)
• Thyroid Neoplasms (drug therapy, genetics, metabolism, pathology)
• Tumor Cells, Cultured
• Vemurafenib