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 KrasG12V/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. Sanclemente et al. generate oncogenic Kras mice that allow inducible deletion of Raf1, encoding c-RAF, and/or Braf in established KrasG12V or KrasG12V;Trp53−/− lung tumors. They show that systemic c-RAF ablation has limited toxicity and leads to significant tumor regression without having an impact on MAPK activity.
Sanclemente, M., Francoz, S., Esteban-Burgos, L., Bousquet-Mur, E., Djurec, M., Lopez-Casas, P. P., … Barbacid, M. (2018). c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling. Cancer Cell, 33(2), 217-228.e4. https://doi.org/10.1016/j.ccell.2017.12.014