BRAF mutation predicts sensitivity to MEK inhibition.

Nature
Authors
Keywords
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.

Year of Publication
2006
Journal
Nature
Volume
439
Issue
7074
Pages
358-62
Date Published
2006 Jan 19
ISSN
1476-4687
URL
DOI
10.1038/nature04304
PubMed ID
16273091
PubMed Central ID
PMC3306236
Links
Grant list
P01 CA094060 / CA / NCI NIH HHS / United States
P01 CA094060-01A1 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States