c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling

Cancer Cell. 2018 Feb 12;33(2):217-228.e4. doi: 10.1016/j.ccell.2017.12.014.

Manuel Sanclemente ¹, Sarah Francoz ¹, Laura Esteban-Burgos ¹, Emilie Bousquet-Mur ¹, Magdolna Djurec ¹, Pedro P Lopez-Casas ², Manuel Hidalgo ², Carmen Guerra ¹, Matthias Drosten ¹, Monica Musteanu ³, Mariano Barbacid ⁴

Affiliations

1 Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
2 Clinical Research Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
3 Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain. Electronic address: mmusteanu@cnio.es.
4 Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain. Electronic address: mbarbacid@cnio.es.

PMID: 29395869 DOI: 10.1016/j.ccell.2017.12.014

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.

Keywords

Kras oncogene; MAPK signaling; c-RAF; lung cancer; mouse models of cancer; therapy strategy; toxicity.

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