title: The BRAFT1799A mutation confers sensitivity of thyroid cancer cells to the BRAFV600E inhibitor PLX4032 (RG7204).
abstract: Aberrant signaling of the Ras-Raf-MEK-ERK (MAP kinase) pathway driven by the mutant kinase BRAF(V600E), as a result of the BRAF(T1799A) mutation, plays a fundamental role in thyroid tumorigenesis. This study investigated the therapeutic potential of a BRAF(V600E)-selective inhibitor, PLX4032 (RG7204), for thyroid cancer by examining its effects on the MAP kinase signaling and proliferation of 10 thyroid cancer cell lines with wild-type BRAF or BRAF(T1799A) mutation. We found that PLX4032 could effectively inhibit the MAP kinase signaling, as reflected by the suppression of ERK phosphorylation, in cells harboring the BRAF(T1799A) mutation. PLX4032 also showed a potent and BRAF mutation-selective inhibition of cell proliferation in a concentration-dependent manner. PLX4032 displayed low IC(50) values (0.115-1.156μM) in BRAF(V600E) mutant cells, in contrast with wild-type BRAF cells that showed resistance to the inhibitor with high IC(50) values (56.674-1349.788μM). Interestingly, cells with Ras mutations were also sensitive to PLX4032, albeit moderately. Thus, this study has confirmed that the BRAF(T1799A) mutation confers cancer cells sensitivity to PLX4032 and demonstrated its specific potential as an effective and BRAF(T1799A) mutation-selective therapeutic agent for thyroid cancer.
authors.affiliation: Division of Head and Neck Cancer Research, Department of Otolaryngology and Head & Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Xing
authors.forename: Ruixin
authors.initials: R
authors.lastname: Liu
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
authors.forename: Barry
authors.initials: B
authors.lastname: Trink
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf