Cited by 120Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingLung Cancer Treatments and Mutations

c-RAF ablation induces regression of advanced Kras/Trp53 mutant lung adenocarcinomas by a mechanism independent of MAPK signaling

Open access
Sanclemente, Manuel, Francoz, Sarah, Esteban-Burgos, Laura, Bousquet-Mur, Emilie, Djurec, Magdolna, Lopez-Casas, Pedro P., Hidalgo, Manuel, Guerra, Carmen +3 more·2018·Cancer Cell

Abstract

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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Crossref · 10.1016/j.ccell.2017.12.014

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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
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
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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