BRAF mutation predicts sensitivity to MEK inhibition Academic Article uri icon

Overview

MeSH Major

  • Mitogen-Activated Protein Kinase Kinases
  • Mutation
  • Proto-Oncogene Proteins B-raf

abstract

  • The kinase pathway comprising RAS, RAF, mitogen-activated protein kinase kinase (MEK) and extracellular signal regulated kinase (ERK) is activated in most human tumours, often through gain-of-function mutations of RAS and RAF family members. Using small-molecule inhibitors of MEK and an integrated genetic and pharmacologic analysis, we find that mutation of BRAF is associated with enhanced and selective sensitivity to MEK inhibition when compared to either 'wild-type' cells or cells harbouring a RAS mutation. This MEK dependency was observed in BRAF mutant cells regardless of tissue lineage, and correlated with both downregulation of cyclin D1 protein expression and the induction of G1 arrest. Pharmacological MEK inhibition completely abrogated tumour growth in BRAF mutant xenografts, whereas RAS mutant tumours were only partially inhibited. These data suggest an exquisite dependency on MEK activity in BRAF mutant tumours, and offer a rational therapeutic strategy for this genetically defined tumour subtype.

publication date

  • January 19, 2006

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3306236

Digital Object Identifier (DOI)

  • 10.1038/nature04304

PubMed ID

  • 16273091

Additional Document Info

start page

  • 358

end page

  • 62

volume

  • 439

number

  • 7074