RANKL Signaling Sustains Primary Tumor Growth in Genetically Engineered Mouse Models of Lung Adenocarcinoma.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_138B2BF10004
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
RANKL Signaling Sustains Primary Tumor Growth in Genetically Engineered Mouse Models of Lung Adenocarcinoma.
Périodique
Journal of thoracic oncology
Auteur⸱e⸱s
Faget J., Contat C., Zangger N., Peters S., Meylan E.
ISSN
1556-1380 (Electronic)
ISSN-L
1556-0864
Statut éditorial
Publié
Date de publication
03/2018
Peer-reviewed
Oui
Volume
13
Numéro
3
Pages
387-398
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
NSCLC is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy.
Receptor activator of NF-κB gene (RANK) and receptor activator of NF-κB ligand gene (RANKL) expression in human lung adenocarcinoma was interrogated from publicly available gene expression data sets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using microcomputed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial.
In human lung adenocarcinoma data sets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co-occurring KRAS and liver kinase B1 gene (LKB1) mutations. In Kras <sup>LSL-G12D/WT</sup> , Kras <sup>LSL-G12D/WT</sup> ; Lkb1 <sup>Flox/Flox</sup> and Kras <sup>LSL-G12D/WT</sup> ; p53 <sup>Flox/Flox</sup> mouse models of lung adenocarcinoma, we monitored an impaired progression of tumors upon RANKL blockade. Despite elevated expression of RANKL and RANK in immune cells, treatment response was not associated with major changes in the tumor immune microenvironment. Combined RANK-Fc with cisplatin revealed increased efficacy compared with that of single agents in p53- but not in Lkb1-deficient tumors.
RANKL blocking agents impair the growth of primary lung tumors in several mouse models of lung adenocarcinoma and suggest that patients with KRAS-mutant lung tumors will benefit from such treatments.

Mots-clé
RANK ligand, genetically engineered mouse models, lung adenocarcinoma, preclinical trial, Genetically engineered mouse models, Lung adenocarcinoma, Preclinical trial
Pubmed
Web of science
Open Access
Oui
Création de la notice
14/12/2017 17:51
Dernière modification de la notice
20/08/2019 12:42
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