• Login
    View Item 
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of ChristieCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsThis CollectionTitleAuthorsIssue DateSubmit DateSubjects

    My Account

    LoginRegister

    Local Links

    The Christie WebsiteChristie Library and Knowledge Service

    Statistics

    Display statistics

    A Braf kinase-inactive mutant induces lung adenocarcinoma.

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    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
    Show allShow less
    Affiliation
    Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain
    Issue Date
    2017-08-10
    
    Metadata
    Show full item record
    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.
    Citation
    A Braf kinase-inactive mutant induces lung adenocarcinoma. 2017, 548 (7666):239-243 Nature
    Journal
    Nature
    URI
    http://hdl.handle.net/10541/620557
    DOI
    10.1038/nature23297
    PubMed ID
    28783725
    Type
    Article
    Language
    en
    ISSN
    1476-4687
    ae974a485f413a2113503eed53cd6c53
    10.1038/nature23297
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

    entitlement

    Related articles

    • Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models.
    • Authors: Ji H, Wang Z, Perera SA, Li D, Liang MC, Zaghlul S, McNamara K, Chen L, Albert M, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Thomas RK, Garraway LA, Jänne PA, Johnson BE, Chin L, Wong KK
    • Issue date: 2007 May 15
    • Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium.
    • Authors: Villaruz LC, Socinski MA, Abberbock S, Berry LD, Johnson BE, Kwiatkowski DJ, Iafrate AJ, Varella-Garcia M, Franklin WA, Camidge DR, Sequist LV, Haura EB, Ladanyi M, Kurland BF, Kugler K, Minna JD, Bunn PA, Kris MG
    • Issue date: 2015 Feb 1
    • MEK1/2 inhibition elicits regression of autochthonous lung tumors induced by KRASG12D or BRAFV600E.
    • Authors: Trejo CL, Juan J, Vicent S, Sweet-Cordero A, McMahon M
    • Issue date: 2012 Jun 15
    • Mutationally activated PIK3CA(H1047R) cooperates with BRAF(V600E) to promote lung cancer progression.
    • Authors: Trejo CL, Green S, Marsh V, Collisson EA, Iezza G, Phillips WA, McMahon M
    • Issue date: 2013 Nov 1
    • Ras effector mutant expression suggest a negative regulator inhibits lung tumor formation.
    • Authors: Vandal G, Geiling B, Dankort D
    • Issue date: 2014
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.