The BRAFT1799A mutation confers sensitivity of thyroid cancer cells to the BRAFV600E inhibitor PLX4032 (RG7204)

Joanna Xing, Ruixin Liu, Mingzhao Xing, Barry Trink

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant signaling of the Ras-Raf-MEK-ERK (MAP kinase) pathway driven by the mutant kinase BRAFV600E, as a result of the BRAFT1799A mutation, plays a fundamental role in thyroid tumorigenesis. This study investigated the therapeutic potential of a BRAFV600E-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 BRAFT1799A mutation. We found that PLX4032 could effectively inhibit the MAP kinase signaling, as reflected by the suppression of ERK phosphorylation, in cells harboring the BRAFT1799A mutation. PLX4032 also showed a potent and BRAF mutation-selective inhibition of cell proliferation in a concentration-dependent manner. PLX4032 displayed low IC50 values (0.115-1.156μM) in BRAFV600E mutant cells, in contrast with wild-type BRAF cells that showed resistance to the inhibitor with high IC50 values (56.674-1349.788μM). Interestingly, cells with Ras mutations were also sensitive to PLX4032, albeit moderately. Thus, this study has confirmed that the BRAFT1799A mutation confers cancer cells sensitivity to PLX4032 and demonstrated its specific potential as an effective and BRAFT1799A mutation-selective therapeutic agent for thyroid cancer.

Original languageEnglish (US)
Pages (from-to)958-962
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume404
Issue number4
DOIs
StatePublished - Jan 28 2011

Keywords

  • BRAF inhibitor
  • BRAF mutation
  • Genetic-dependent therapy
  • PLX4032
  • RG7204
  • Thyroid cancer

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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