RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
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DOI：
10.1038/nature08833
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发表时间：
2010-03-18
期刊：
影响因子：
64.8
通讯作者：
Malek, Shiva
中科院分区：
文献类型：
--
作者：
Hatzivassiliou, Georgia;Song, Kyung;Malek, Shiva
KRAS 和 BRAF 的激活突变分别存在于超过 30% 的人类肿瘤和 40% 的黑色素瘤中，因此针对该通路可能具有广泛的治疗效果 (1)。小分子 ATP 竞争性 RAF 激酶抑制剂对突变 BRAF(V600E) 肿瘤具有有效的抗肿瘤作用，但与丝裂原激活蛋白激酶激酶 (MEK) 抑制剂相比，尽管 RAF 作为 RAS 下游和 MEK2,3 上游的关键效应器，但对 RAS 突变肿瘤模型并不有效。在这里，我们证明 ATP 竞争性 RAF 抑制剂具有两种相反的作用机制，具体取决于细胞环境。在 BRAF(V600E) 肿瘤中，RAF 抑制剂有效阻断丝裂原激活蛋白激酶 (MAPK) 信号通路并减少肿瘤生长。值得注意的是，在 KRAS 突变体和 RAS/RAF 野生型肿瘤中，RAF 抑制剂以 RAS 依赖性方式激活 RAF-MEK-ERK 通路，从而增强某些异种移植模型中的肿瘤生长。抑制剂结合通过诱导二聚化、膜定位以及与 RAS-GTP 的相互作用来激活野生型 RAF 同工型。这些事件的发生与激酶抑制无关，而是与抑制剂对 RAF 激酶结构域的直接构象效应有关。基于这些发现，我们证明 ATP 竞争性激酶抑制剂可以作为信号通路的抑制剂或激活剂具有相反的功能，具体取决于细胞环境。此外，这项工作为 ATP 竞争性 RAF 抑制剂的治疗用途提供了新的见解。
Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects(1). Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK2,3. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.