BRAF mutation predicts sensitivity to MEK inhibition

David B. Solit, Levi A. Garraway, Christine A. Pratilas, Ayana Sawai, Gad Getz, Andrea Basso, Qing Ye, Jose M. Lobo, Yuhong She, Iman Osman, Todd R. Golub, Judith Sebolt-Leopold, William R. Sellers, Neal Rosen

Research output: Contribution to journalArticle

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 members1. 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.

Original languageEnglish (US)
Pages (from-to)358-362
Number of pages5
JournalNature
Volume439
Issue number7074
DOIs
StatePublished - Jan 19 2006
Externally publishedYes

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ASJC Scopus subject areas

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Cite this

Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., Golub, T. R., Sebolt-Leopold, J., Sellers, W. R., & Rosen, N. (2006). BRAF mutation predicts sensitivity to MEK inhibition. Nature, 439(7074), 358-362. https://doi.org/10.1038/nature04304