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- Title
BRAF mutation predicts sensitivity to MEK inhibition.
- Authors
Solit, David B; Garraway, Levi A; Pratilas, Christine A; Sawai, Ayana; Getz, Gad; Basso, Andrea; Ye, Qing; Lobo, Jose M; She, Yuhong; Osman, Iman; Golub, Todd R; Sebolt-Leopold, Judith; Sellers, William R; Rosen, Neal
- 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
Nature, 2006, Vol 439, Issue 7074, p358
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature04304