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 members. 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.
Solit
David B
DB
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Garraway
Levi A
LA
Pratilas
Christine A
CA
Sawai
Ayana
A
Getz
Gad
G
Basso
Andrea
A
Ye
Qing
Q
Lobo
Jose M
JM
She
Yuhong
Y
Osman
Iman
I
Golub
Todd R
TR
Sebolt-Leopold
Judith
J
Sellers
William R
WR
Rosen
Neal
N
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D019938:Cyclin D1; C506614:mirdametinib; D004159:Diphenylamine; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases