BRAF mutation predicts sensitivity to MEK inhibition Journal Article
| Authors: | 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. |
| Article Title: | BRAF mutation predicts sensitivity to MEK inhibition |
| 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. © 2006 Nature Publishing Group. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; mutation; nonhuman; drug targeting; cell proliferation; mouse; animals; mice; enzyme inhibition; pharmacodynamics; mitogen activated protein kinase inhibitor; animal experiment; cancer cell culture; tumor xenograft; xenograft model antitumor assays; enzyme activity; cell line, tumor; mutational analysis; phosphorylation; prediction; animalia; cancer inhibition; correlation analysis; tumors; cell cycle arrest; down regulation; enzyme kinetics; cyclin d1; medicine; b raf kinase; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; mutagenesis; cell cycle g1 phase; g1 phase; enzymes; proto-oncogene proteins b-raf; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; cells; 2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; benzamides; diphenylamine; extracellular signal regulated kinase (erk); kinase pathway; mutant cells |
| Journal Title: | Nature |
| Volume: | 439 |
| Issue: | 7074 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2006-01-19 |
| Start Page: | 358 |
| End Page: | 362 |
| Language: | English |
| DOI: | 10.1038/nature04304 |
| PUBMED: | 16273091 |
| PROVIDER: | scopus |
| PMCID: | PMC3306236 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 512" - "Export Date: 4 June 2012" - "CODEN: NATUA" - "Source: Scopus" |
