C-Raf Is Required for the Initiation of Lung Cancer by K-RasG12D

Abstract

The Ras/Raf/MEK/ERK (extracellular signal–regulated kinase) 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 mitogen-activated protein kinase pathway are now available for clinical investigation and thus the determination of the importance of each of the kinases in oncogenesis is paramount. We investigated the role of two Raf kinases, B-Raf and C-Raf, in Ras oncogenesis, and found that although 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-Ras^G12D in primary epithelial cells. Furthermore, in a lung cancer mouse model, C-Raf is essential for tumor initiation by oncogenic K-Ras^G12D, whereas B-Raf is dispensable for this process. Our findings reveal that K-Ras^G12D 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. Significance: Ras is one of the most prevalent oncogenes in human cancer; however, it is considered “undruggable.” Therefore, increasing our understanding of the importance of Ras effectors, including the Raf/MEK/ERK pathway, will create novel avenues for therapeutic intervention. Cancer Discovery; 1(2); 128–36. © 2011 AACR. Read the Commentary on this article by Rebocho and Marais, p. 98 This article is highlighted in the In This Issue feature, p. 91