B-RAF is a therapeutic target in melanoma
B-RAF is a therapeutic target in melanoma
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DOI：
10.1038/sj.onc.1207785
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发表时间：
2004-08-19
期刊：
影响因子：
8
通讯作者：
Marais, R
中科院分区：
文献类型：
--
作者：
Karasarides, M;Chiloeches, A;Marais, R
B-RAF 是一种丝氨酸/苏氨酸特异性蛋白激酶，在大约 70% 的人类黑色素瘤中发生突变。然而，这种信号分子在癌症中的作用尚不清楚。在这里，我们表明 ERK 在表达致癌 B-RAF 的黑色素瘤细胞中被组成型激活，并且这种活性是增殖所必需的。 siRNA 消耗 B-RAF 会阻断 ERK 活性，而 A-RAF 和 C-RAF 消耗不会影响 ERK 信号传导。 B-RAF 耗竭会抑制三种黑色素瘤细胞系中的 DNA 合成并诱导细胞凋亡，我们表明 RAF 抑制剂 BAY43-9006 也会阻断这些细胞中的 ERK 活性、抑制 DNA 合成并诱导细胞死亡。 BAY43-9006 体内靶向 B-RAF 信号传导，并诱导黑色素瘤异种移植物的生长显着延迟。我们的数据表明，致癌 B-RAF 激活 ERK 信号传导、诱导增殖并保护细胞免于凋亡，证明它是一个重要的治疗靶点，从而为黑色素瘤和其他癌症的临床管理提供新策略。
B-RAF is a serine/threonine-specific protein kinase that is mutated in approximately 70% of human melanomas. However, the role of this signalling molecule in cancer is unclear. Here, we show that ERK is constitutively activated in melanoma cells expressing oncogenic B-RAF and that this activity is required for proliferation. B-RAF depletion by siRNA blocks ERK activity, whereas A-RAF and C-RAF depletion do not affect ERK signalling. B-RAF depletion inhibits DNA synthesis and induces apoptosis in three melanoma cell lines and we show that the RAF inhibitor BAY43-9006 also blocks ERK activity, inhibits DNA synthesis and induces cell death in these cells. BAY43-9006 targets B-RAF signalling in vivo and induces a substantial growth delay in melanoma tumour xenografts. Our data demonstrate that oncogenic B-RAF activates ERK signalling, induces proliferation and protects cells from apoptosis, demonstrating that it is an important therapeutic target and thus provides novel strategies for clinical management of melanoma and other cancers.