Disruption of mutated BRAF signaling modulates thyroid cancer phenotype

BMC Research Notes

Raj K Tiwari³  Jan Geliebter³  Edward J Shin¹  Robert Bednarczyk³  Andrea L George³  Neha Tuli³  Robert Suriano³  Hong Zhao²  Zbigniew Darzynkiewicz²  Shilpi Rajoria³  Elyse K Hanly³ 

[1] Department of Otolaryngology, New York Eye and Ear Infirmary, New York, New York 10003, USA;Department of Pathology, New York Medical College, Valhalla, New York 10595, USA;Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, USA

关键词: Kinase inhibitors;    Targeted therapy;    MAPK signal transduction pathway;    PLX4032;    BRAFV600E mutation;    Thyroid cancer;   

Others  :  1134118
DOI  :  10.1186/1756-0500-7-187

 received in 2013-06-26, accepted in 2014-03-19,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Hanly et al.; licensee BioMed Central Ltd.

【 图 表 】

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