1. Department of Medicine,
2. Department of Pediatrics, and
3. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
4. Department of Medical Oncology and
5. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
6. Broad Institute of Harvard and MIT, 320 Charles Street, Cambridge, Massachusetts 02141, USA
7. Departments of Medicine and Urology, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA
8. Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
9. †Present address: Schering-Plough, 2015 Galloping Hill Rd, Kenilworth, New Jersey 07033, USA

Correspondence to: Neal Rosen^1,3 Correspondence and requests for materials should be addressed to N.R. (Email: rosenn@mskcc.org).

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.

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