c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma

Cancer Cell. 2011 May 17;19(5):652-63. doi: 10.1016/j.ccr.2011.04.002. Epub 2011 Apr 21.

Abstract

We have investigated the role of individual members of the Raf/Mek/Erk cascade in the onset of K-Ras oncogene-driven non-small cell lung carcinoma (NSCLC). Ablation of Erk1 or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet, elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mek kinases. Ablation of B-Raf had no significant effect on tumor development. However, c-Raf expression was absolutely essential for the onset of NSCLC. Interestingly, concomitant elimination of c-Raf and B-Raf in adult mice had no deleterious consequences for normal homeostasis. These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cellular Senescence
  • Fibroblasts / enzymology
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genes, ras*
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • MAP Kinase Kinase 1 / deficiency
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 2 / deficiency
  • MAP Kinase Kinase 2 / genetics
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / deficiency
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 3 / deficiency
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Proto-Oncogene Proteins B-raf / deficiency
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Proto-Oncogene Proteins c-raf / deficiency
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism*
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Burden

Substances

  • BRAF protein, human
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Map2k1 protein, mouse
  • Map2k2 protein, mouse