C-Raf is required for the initiation of lung cancer by K-Ras(G12D).
C-Raf is required for the initiation of lung cancer by K-Ras(G12D).
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DOI：
10.1158/2159-8290.cd-10-0044
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发表时间：
2011-07
期刊：
影响因子：
28.2
通讯作者：
Tuveson DA
中科院分区：
文献类型：
--
作者：
Karreth FA;Frese KK;DeNicola GM;Baccarini M;Tuveson DA
Ras/Raf/MEK/ERK 通路主要负责后生动物的有丝分裂发生，该通路的突变激活在癌症中很常见。现在有多种针对 MAPK 通路的选择性化学抑制剂可用于临床研究，因此确定每种激酶在肿瘤发生中的重要性至关重要。在这里，我们研究了两种 Raf 激酶 B-Raf 和 C-Raf 在 Ras 肿瘤发生中的作用，发现虽然 B-Raf 和 C-Raf 在原代间充质细胞中具有重叠功能，但 K-RasG12D 在原代上皮细胞中的增殖作用需要 C-Raf 而不是 B-Raf。此外，在肺癌小鼠模型中，C-Raf 对于致癌 K-RasG12D 引发肿瘤至关重要，而 B-Raf 对于这一过程是可有可无的。我们的研究结果表明，K-RasG12D 主要通过 C-Raf 引发其致癌作用，并表明选择性 C-Raf 抑制可以作为 K-Ras 依赖性癌症的治疗策略进行探索。
The Ras/Raf/MEK/ERK pathway is primarily responsible for mitogenesis in metazoans, and mutational activation of this pathway is common in cancer. A variety of selective chemical inhibitors directed against the MAPK pathway are now available for clinical investigation and thus the determination of the importance of each of the kinases in oncogenesis is paramount. Here, we investigated the role of two Raf kinases, B-Raf and C-Raf, in Ras oncogenesis, and find that while B-Raf and C-Raf have overlapping functions in primary mesenchymal cells, C-Raf but not B-Raf is required for the proliferative effects of K-RasG12D in primary epithelial cells. Furthermore, in a lung cancer mouse model, C-Raf is essential for tumor initiation by oncogenic K-RasG12D, while B-Raf is dispensable for this process. Our findings reveal that K-RasG12D elicits its oncogenic effects primarily through C-Raf and suggest that selective C-Raf inhibition could be explored as a therapeutic strategy for K-Ras dependent cancers.