A Braf kinase-inactive mutant induces lung adenocarcinoma.

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. Inactivat...

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Autores: Nieto, Patricia, Ambrogio, Chiara, Esteban-Burgos, Laura, Gómez-López, Gonzalo, Blasco, María Teresa, Yao, Zhan, Marais, Richard, Rosen, Neal, Chiarle, Roberto, Pisano, David G, Barbacid, Mariano, Santamaría, David
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/25313
Acceso en línea:https://hdl.handle.net/20.500.12105/25313
Access Level:acceso abierto
Palabra clave:TUMOR-SUPPRESSOR ACTIVITY
K-RAS ONCOGENE
MOUSE MODEL
C-RAF
B-RAF
CANCER
CELLS
PROTEIN
PROGRESSION
INHIBITORS
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network_acronym_str ES
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repository_id_str
spelling A Braf kinase-inactive mutant induces lung adenocarcinoma.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, DavidTUMOR-SUPPRESSOR ACTIVITYK-RAS ONCOGENEMOUSE MODELC-RAFB-RAFCANCERCELLSPROTEINPROGRESSIONINHIBITORSThe 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.Nature Publishing GroupUnión Europea. Comisión Europea. European Research Council (ERC)Ministerio de Ciencia e Innovación (España)Fundación AXANational Institutes of Health (Estados Unidos)Asociación Española Contra el Cáncer20242024-10-2820172017-08-1020172017-08-10research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttps://hdl.handle.net/20.500.12105/25313reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 242965European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 250297Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available SAF2011-30173 INHIBICION DE LA SEÑALIZACION DEL ONCOGEN K-RAS EN CANCERMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available SAF2014-59864-R UN ABORDAJE MULTIDISPLINAR PARA DESARROLLAR NUEVAS VIAS TERAPEUTICAS CONTRA EL ADENOCARCINOMA DUCTAL DE PANCREASEuropean Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 260791open accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/253132026-06-12T12:43:37Z
dc.title.none.fl_str_mv A Braf kinase-inactive mutant induces lung adenocarcinoma.
title A Braf kinase-inactive mutant induces lung adenocarcinoma.
spellingShingle A Braf kinase-inactive mutant induces lung adenocarcinoma.
Nieto, Patricia
TUMOR-SUPPRESSOR ACTIVITY
K-RAS ONCOGENE
MOUSE MODEL
C-RAF
B-RAF
CANCER
CELLS
PROTEIN
PROGRESSION
INHIBITORS
title_short A Braf kinase-inactive mutant induces lung adenocarcinoma.
title_full A Braf kinase-inactive mutant induces lung adenocarcinoma.
title_fullStr A Braf kinase-inactive mutant induces lung adenocarcinoma.
title_full_unstemmed A Braf kinase-inactive mutant induces lung adenocarcinoma.
title_sort A Braf kinase-inactive mutant induces lung adenocarcinoma.
dc.creator.none.fl_str_mv Nieto, Patricia
Ambrogio, Chiara
Esteban-Burgos, Laura
Gómez-López, Gonzalo
Blasco, María Teresa
Yao, Zhan
Marais, Richard
Rosen, Neal
Chiarle, Roberto
Pisano, David G
Barbacid, Mariano
Santamaría, David
Nieto, Patricia
Ambrogio, Chiara
Esteban-Burgos, Laura
Gómez-López, Gonzalo
Blasco, María Teresa
Yao, Zhan
Marais, Richard
Rosen, Neal
Chiarle, Roberto
Pisano, David G
Santamaría, David
author Nieto, Patricia
author_facet Nieto, Patricia
Ambrogio, Chiara
Esteban-Burgos, Laura
Gómez-López, Gonzalo
Blasco, María Teresa
Yao, Zhan
Marais, Richard
Rosen, Neal
Chiarle, Roberto
Pisano, David G
Barbacid, Mariano
Santamaría, David
author_role author
author2 Ambrogio, Chiara
Esteban-Burgos, Laura
Gómez-López, Gonzalo
Blasco, María Teresa
Yao, Zhan
Marais, Richard
Rosen, Neal
Chiarle, Roberto
Pisano, David G
Barbacid, Mariano
Santamaría, David
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Unión Europea. Comisión Europea. European Research Council (ERC)
Ministerio de Ciencia e Innovación (España)
Fundación AXA
National Institutes of Health (Estados Unidos)
Asociación Española Contra el Cáncer
dc.subject.none.fl_str_mv TUMOR-SUPPRESSOR ACTIVITY
K-RAS ONCOGENE
MOUSE MODEL
C-RAF
B-RAF
CANCER
CELLS
PROTEIN
PROGRESSION
INHIBITORS
topic TUMOR-SUPPRESSOR ACTIVITY
K-RAS ONCOGENE
MOUSE MODEL
C-RAF
B-RAF
CANCER
CELLS
PROTEIN
PROGRESSION
INHIBITORS
description 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.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017-08-10
2017
2017-08-10
2024
2024-10-28
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/25313
url https://hdl.handle.net/20.500.12105/25313
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 242965
European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 250297
Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available SAF2011-30173 INHIBICION DE LA SEÑALIZACION DEL ONCOGEN K-RAS EN CANCER
Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available SAF2014-59864-R UN ABORDAJE MULTIDISPLINAR PARA DESARROLLAR NUEVAS VIAS TERAPEUTICAS CONTRA EL ADENOCARCINOMA DUCTAL DE PANCREAS
European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 260791
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407683318120448
score 15,812429

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