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BRAF mutation predicts sensitivity to MEK inhibition


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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Figure 1: The BRAF(V600E) mutation confers sensitivity to the MEK inhibitor CI-1040.
Figure 2: Chemical sensitivity associated with mutant BRAF and RAS class distinctions.
Figure 3: MEK inhibition causes loss of D-cyclin expression, RB hypophosphorylation and G1 arrest in BRAF mutant cancer cells.
Figure 4: PD0325901 completely suppresses the growth of BRAF(V600E) mutant xenografts.

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The authors thank H. Ju, W. L. Wong and H. Tseng for technical assistance. This work was supported by grants from the National Institutes of Health (L.A.G., C.A.P., G.G., T.R.G., W.R.S. and N.R.), the William H. Goodwin and Alice Goodwin Foundation for Cancer Research, the MSKCC Experimental Therapeutics Program (D.B.S. and N.R.), the Waxman Foundation (D.B.S. and N.R.), the Howard Hughes Medical Institute (G.G. and T.R.G.), Golfers Against Cancer (D.B.S. and N.R.) and the American Society of Clinical Oncology (D.B.S. and C.A.P.).

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Correspondence to Neal Rosen.

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J.S.-L. is an employee of Pfizer Global Research.

Supplementary information

Supplementary Figure Legends

Legends to accompany the Supplementary Figures and Supplementary Table. (DOC 25 kb)

Supplementary Table 1

Significant Compounds Following Supervised Pharmacologic Analysis of BRAF(V600E) Mutation in NCI60 Cancer Cell Lines. (PDF 55 kb)

Supplementary Figure 1

Hypothemycin causes downregulation of p-ERK and cyclin D1 expression in BRAF(V600E) mutant cells. (PDF 213 kb)

Supplementary Figure 2

PD0325901 selectively inhibits the growth of BRAF mutant cell lines. (PDF 61 kb)

Supplementary Figure 3

Sensitivity of Colo205 and SKMEL30 xenograft tumours to the MEK inhibitor PD0325901. (PDF 16 kb)

Supplementary Figure 4

dSensitivity of xenograft tumours to PD0325901 does not correlate with basal levels of p-ERK. (PDF 137 kb)

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Solit, D., Garraway, L., Pratilas, C. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 (2006).

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