BRAF mutation predicts sensitivity to MEK inhibition
BRAF mutation predicts sensitivity to MEK inhibition
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DOI：
10.1038/nature04304
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发表时间：
2006-01-19
期刊：
影响因子：
64.8
通讯作者：
Rosen, N
中科院分区：
文献类型：
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作者：
Solit, DB;Garraway, LA;Rosen, N
由RAS、RAF、丝裂原活化蛋白激酶（MEK）和细胞外信号调节激酶（ERK）组成的激酶途径在大多数人类肿瘤中被激活，通常是通过RAS和RAF家族成员的功能获得性突变(1)。利用MEK的小分子抑制剂和综合遗传和药理学分析，我们发现与“野生型”细胞或含有RAS突变的细胞相比，BRAF突变与MEK抑制的增强和选择性敏感性相关。无论组织谱系如何，在BRAF突变细胞中都观察到这种MEK依赖性，并且与cyclin D1蛋白表达下调和G1阻滞的诱导相关。药物MEK抑制完全消除了BRAF突变异种移植物的肿瘤生长，而RAS突变肿瘤仅部分受到抑制。这些数据表明BRAF突变肿瘤对MEK活性的高度依赖性，并为这种基因定义的肿瘤亚型提供了合理的治疗策略。
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(1). 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.