The Institute of Cancer Research, Signal Transduction Team, Section of Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.
Cell. 2010 Jan 22;140(2):209-21. doi: 10.1016/j.cell.2009.12.040.
We describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence of oncogenic RAS. We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF activation, and MEK-ERK signaling. This does not occur when oncogenic BRAF is inhibited, demonstrating that BRAF inhibition per se does not drive pathway activation; it only occurs when BRAF is inhibited in the presence of oncogenic RAS. Kinase-dead BRAF mimics the effects of the BRAF-selective drugs and kinase-dead Braf and oncogenic Ras cooperate to induce melanoma in mice. Our data reveal another paradigm of BRAF-mediated signaling that promotes tumor progression. They highlight the importance of understanding pathway signaling in clinical practice and of genotyping tumors prior to administering BRAF-selective drugs, to identify patients who are likely to respond and also to identify patients who may experience adverse effects.
我们描述了一种在致癌性 RAS 存在的情况下，由激酶失活 BRAF 介导的肿瘤发生机制。我们表明，选择性抑制 BRAF 的药物会驱动 RAS 依赖性 BRAF 与 CRAF 的结合、CRAF 的激活以及 MEK-ERK 信号转导。当抑制致癌性 BRAF 时，这种情况不会发生，这表明 BRAF 抑制本身不会驱动通路激活；只有当 BRAF 在致癌性 RAS 存在的情况下被抑制时才会发生。激酶失活 BRAF 模拟了 BRAF 选择性药物的作用，并且激酶失活 Braf 和致癌性 Ras 合作诱导小鼠黑色素瘤的发生。我们的数据揭示了另一种促进肿瘤进展的 BRAF 介导的信号转导模式。它们强调了在临床实践中理解通路信号的重要性，以及在给予 BRAF 选择性药物之前对肿瘤进行基因分型的重要性，以识别可能有反应的患者，同时也识别可能出现不良反应的患者。
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