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C-Raf Is Required for the Initiation of Lung Cancer by K-RasG12D
Open accessPublished version of a preprint
Abstract
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-RasG12D in primary epithelial cells. Furthermore, in a lung cancer mouse model, C-Raf is essential for tumor initiation by oncogenic K-RasG12D, whereas 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. 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
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“Together, these studies provided compelling evidence that C-Raf, but not B-Raf or A-Raf, may mediate the oncogenic signaling in KRAS-driven cancer.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [75]
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“Recent studies showed that C-RAF rather than B-RAF plays a crucial role in mediating KRAS oncogenic signaling (74, 75).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [75]
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Metadata
- Authors
- Karreth, F. A., Frese, K. K., DeNicola, G. M., Baccarini, M., & Tuveson, D. A.
- Affiliations
- University of Vienna (AT)
- Venue
- Cancer Discovery
- Published
- 2011-07-01
- Volume
- 1
- Issue
- 2
- Pages
- 128-136
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3203527
- OpenAlex
- W2133177414
- Cited by
- 149
- References
- 29
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 12 · 2022: 9 · 2021: 13 · 2020: 8 · 2019: 8 · 2018: 12 · 2017: 11 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 9 · 2012: 8
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (A10211)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Raf-1, BRAF, lung cancer, RAS/MAPK pathway, carcinogenesis, tumor initiation, Raf kinase inhibition, Ras effectors, epithelial cell proliferation
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Epithelial Cells, Fibroblasts, Lung, Lung Neoplasms, Mutation, Transformation, Genetic, ras Proteins, Proto-Oncogene Proteins c-raf, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Cell Growth Processes, Mice, Mice, 129 Strain, Mesenchymal Stem Cells
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