Nieto, PatriciaAmbrogio, ChiaraEsteban-Burgos, LauraGómez-López, GonzaloBlasco, María TeresaYao, ZhanMarais, RichardRosen, NealChiarle, RobertoPisano, David GBarbacid, MarianoSantamaría, DavidNieto, PatriciaAmbrogio, ChiaraEsteban-Burgos, LauraGómez-López, GonzaloBlasco, María TeresaYao, ZhanMarais, RichardRosen, NealChiarle, RobertoPisano, David GSantamaría, David2024-10-282024-10-282017-08-10Nature . 2017 Aug 10;548(7666):239-243.https://hdl.handle.net/20.500.12105/25313We thank A. de Martino for histopathological evaluation of murine lung tumours. This work was supported by grants to M.B. from the European Research Council (ERC-AG/250297-RAS AHEAD), EU-Framework Programme (HEALTH-F2-2010-259770/LUNGTARGET and HEALTH-2010-260791/EUROCANPLATFORM) and Spanish Ministry of Economy and Competitiveness (SAF2011-30173 and SAF2014-59864-R). M.B. is the recipient of an Endowed Chair from the AXA Research Fund. Funding was also provided by grants to N.R. from the National Institutes of Health (P01 CA129243; R35 CA210085); the Commonwealth Foundation for Cancer Research, the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center and the Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15). Support was also received from the NIH MSKCC Cancer Center Support Grant P30 CA008748. Work in the laboratory of R.C. was supported by grants FP7 ERC-2009-StG (242965-Lunely) and Associazione Italiana per la Ricerca sul Cancro (AIRC) grant IG-12023. P.N. was the recipient of an FPU fellowship from the Spanish Ministry of Education. C.A. was the recipient of a postdoctoral fellowship from the Spanish Association Against Cancer (AECC).The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity, and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.engVoRhttp://creativecommons.org/licenses/by/4.0/TUMOR-SUPPRESSOR ACTIVITYK-RAS ONCOGENEMOUSE MODELC-RAFB-RAFCANCERCELLSPROTEINPROGRESSIONINHIBITORSAttribution 4.0 International287837255487666239-243Naturehttps://pmc.ncbi.nlm.nih.gov/articles/PMC5648056/pdf/nihms908709.pdfopen access