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.
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References
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)
Brose, M. S. et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000 (2002)
Gorden, A. et al. Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res. 63, 3955–3957 (2003)
Crews, C. M., Alessandrini, A. & Erikson, R. L. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258, 478–480 (1992)
Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo . Nature Med. 5, 810–816 (1999)
Ohren, J. F. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nature Struct. Mol. Biol. 11, 1192–1197 (2004)
Mody, N., Leitch, J., Armstrong, C., Dixon, J. & Cohen, P. Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett. 502, 21–24 (2001)
Stinson, S. F. et al. Morphological and immunocytochemical characteristics of human tumour cell lines for use in a disease-oriented anticancer drug screen. Anticancer Res. 12, 1035–1053 (1992)
Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999)
Zhao, A. et al. Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK. J. Antibiot. (Tokyo) 52, 1086–1094 (1999)
Dombrowski, A. et al. Production of a family of kinase-inhibiting lactones from fungal fermentations. J. Antibiot. (Tokyo) 52, 1077–1085 (1999)
Chopra, A. P., Boone, S. A., Liang, X. & Duesbery, N. S. Anthrax lethal factor proteolysis and inactivation of MAPK kinase. J. Biol. Chem. 278, 9402–9406 (2003)
Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo . J. Biol. Chem. 270, 27489–27494 (1995)
Cheng, M., Sexl, V., Sherr, C. J. & Roussel, M. F. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc. Natl Acad. Sci. USA 95, 1091–1096 (1998)
Sebolt-Leopold, J. S. & Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Rev. Cancer 4, 937–947 (2004)
Wellbrock, C. et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res. 64, 2338–2342 (2004)
Karasarides, M. et al. B-RAF is a therapeutic target in melanoma. Oncogene 23, 6292–6298 (2004)
Muise-Helmericks, R. C. et al. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J. Biol. Chem. 273, 29864–29872 (1998)
Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998)
Filmus, J. et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 9, 3627–3633 (1994)
Liu, J. J. et al. Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol. Cell. Biol. 15, 3654–3663 (1995)
Albanese, C. et al. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J. Biol. Chem. 270, 23589–23597 (1995)
Aktas, H., Cai, H. & Cooper, G. M. Ras links growth factor signalling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1. Mol. Cell. Biol. 17, 3850–3857 (1997)
Kerkhoff, E. & Rapp, U. R. Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol. Cell. Biol. 17, 2576–2586 (1997)
Weber, J. D., Raben, D. M., Phillips, P. J. & Baldassare, J. J. Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem. J. 326, 61–68 (1997)
Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045–2057 (2002)
Gonzalez-Garcia, A. et al. RalGDS is required for tumour formation in a model of skin carcinogenesis. Cancer Cell 7, 219–226 (2005)
Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005)
Acknowledgements
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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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). https://doi.org/10.1038/nature04304
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DOI: https://doi.org/10.1038/nature04304
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