title: 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.forename: Elyse K
authors.initials: EK
authors.lastname: Hanly
authors.forename: Shilpi
authors.initials: S
authors.lastname: Rajoria
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Darzynkiewicz
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Robert
authors.initials: R
authors.lastname: Suriano
authors.forename: Neha
authors.initials: N
authors.lastname: Tuli
authors.forename: Andrea L
authors.initials: AL
authors.lastname: George
authors.forename: Robert
authors.initials: R
authors.lastname: Bednarczyk
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Shin
authors.forename: Jan
authors.initials: J
authors.lastname: Geliebter
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, USA. Raj_Tiwari@nymc.edu.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Tiwari
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases