c-RAF ablation induces regression of advanced Kras/Trp53 mutant lung adenocarcinomas by a mechanism independent of MAPK signaling
Open accessAbstract
A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by Kras G12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.
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The therapeutic effect observed by ablation of C-Raf was likely due to disrupting the interaction of the C-Raf protein with other partners, such as BCL2, ASK1, MST2, and ROKα, rather than via modulating the MAPK cascade.
“the therapeutic effect observed by ablation of C-Raf was likely due to disrupting the interaction of the C-Raf protein with other partners, such as BCL2, ASK1, MST2, and ROKα (76), whereas not via modulating MAPK cascade”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [76]
C-Raf, but not B-Raf or A-Raf, may mediate the oncogenic signaling in KRAS-driven cancer.
“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 [76]
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- Authors
- Sanclemente, M., Francoz, S., Esteban-Burgos, L., Bousquet-Mur, E., Djurec, M., Lopez-Casas, P. P., Hidalgo, M., Guerra, C., Drosten, M., Musteanu, M., & Barbacid, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Barbacid, Mariano
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 33
- Issue
- 2
- Pages
- 217-228.e4
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2787649310
- Cited by
- 119
- References
- 29
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 13 · 2023: 20 · 2022: 10 · 2021: 22 · 2020: 9 · 2019: 16 · 2018: 11
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- European Research Council (ERC-2009-AdG/250297-RAS, ERC-2015-AdG/695566)
- EU-Framework Program (HEALTH-F2-2010-259770, HEALTH-2010-260791)
- Spanish Ministry of Economy and Competitiveness (SAF2011-30173, SAF2014-59864-R)
- Autonomous Community of Madrid (S2011/BDM-2470)
- AXA Research Fund
- FEBS
- Instituto de Salud Carlos III
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- KRAS G12V, Trp53 mutation, lung adenocarcinoma, tumor regression, apoptosis, RAF inhibition
- MeSH terms
- Adenocarcinoma of Lung, Animals, Mutation, Proto-Oncogene Proteins, Genes, ras, ras Proteins, Proto-Oncogene Proteins c-raf, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Mice
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