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Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells

Paolo Salerno1, Valentina De Falco, Anna Tamburrino

  • 1Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita Federico II, 80131 Naples, Italy.

The Journal of Clinical Endocrinology and Metabolism
|November 3, 2009
PubMed
Abstract

Insights

BRAF V600E inhibitors PLX4032 and PLX4720 effectively reduced thyroid carcinoma cell proliferation and tumor growth by targeting the BRAF V600E mutation. These findings highlight BRAF as a promising molecular target for thyroid cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The BRAF V600E mutation is a key driver in a majority of thyroid carcinomas.
  • Targeting mutated BRAF presents a potential therapeutic strategy for thyroid cancer.

Purpose of the Study:

  • To investigate the efficacy of BRAF V600E ATP-competitive kinase inhibitors PLX4032 and PLX4720.
  • To evaluate their effects on thyroid carcinoma cell lines with specific oncogenic mutations.

Main Methods:

  • Assessed PLX4032 and PLX4720 activity in thyroid carcinoma cell lines (BRAF V600E, NRAS, KRAS, HRAS, RET/PTC1) and normal thyrocytes.
  • Monitored cell proliferation, ERK1/2 and MEK1/2 phosphorylation, cell-cycle progression, and tumor xenograft growth in mice.

Main Results:

  • Both inhibitors significantly reduced proliferation in BRAF V600E mutant cell lines (EC50 29-113 nm), with minimal effect on normal thyrocytes or other mutant cell lines.
  • Treatment decreased ERK1/2 and MEK1/2 phosphorylation and induced a G1 cell-cycle block in BRAF mutant cells.
  • PLX4032 treatment reduced tumor xenograft size in mice, correlating with decreased phospho-ERK and phospho-MEK levels.

Conclusions:

  • Mutant BRAF is a viable molecular target for thyroid carcinoma therapy.
  • PLX4032 and PLX4720 demonstrate significant anti-tumor activity in preclinical models of BRAF-mutated thyroid cancer.

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