2.50
Hdl Handle:
http://hdl.handle.net/10541/620557
Title:
A Braf kinase-inactive mutant induces lung adenocarcinoma.
Authors:
Nieto, P; Ambrogio, C; Esteban-Burgos, L; Gómez-López, G; Blasco, M; Yao, Z; Marais, Richard; Rosen, N; Chiarle, R; Pisano, D; Barbacid, M; Santamaría, D
Abstract:
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.
Affiliation:
Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain
Citation:
A Braf kinase-inactive mutant induces lung adenocarcinoma. 2017, 548 (7666):239-243 Nature
Journal:
Nature
Issue Date:
10-Aug-2017
URI:
http://hdl.handle.net/10541/620557
DOI:
10.1038/nature23297
PubMed ID:
28783725
Type:
Article
Language:
en
ISSN:
1476-4687
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorNieto, Pen
dc.contributor.authorAmbrogio, Cen
dc.contributor.authorEsteban-Burgos, Len
dc.contributor.authorGómez-López, Gen
dc.contributor.authorBlasco, Men
dc.contributor.authorYao, Zen
dc.contributor.authorMarais, Richarden
dc.contributor.authorRosen, Nen
dc.contributor.authorChiarle, Ren
dc.contributor.authorPisano, Den
dc.contributor.authorBarbacid, Men
dc.contributor.authorSantamaría, Den
dc.date.accessioned2017-09-08T15:04:16Z-
dc.date.available2017-09-08T15:04:16Z-
dc.date.issued2017-08-10-
dc.identifier.citationA Braf kinase-inactive mutant induces lung adenocarcinoma. 2017, 548 (7666):239-243 Natureen
dc.identifier.issn1476-4687-
dc.identifier.pmid28783725-
dc.identifier.doi10.1038/nature23297-
dc.identifier.urihttp://hdl.handle.net/10541/620557-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.rightsArchived with thanks to Natureen
dc.titleA Braf kinase-inactive mutant induces lung adenocarcinoma.en
dc.typeArticleen
dc.contributor.departmentExperimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spainen
dc.identifier.journalNatureen

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