| Added by | Nathalie Bonnefoy |
|---|---|
| Group name | EquipeNB |
| Item Type | Journal Article |
| Title | RANKL Signaling Sustains Primary Tumor Growth in Genetically Engineered Mouse Models of Lung Adenocarcinoma |
| Creator | Faget et al. |
| Author | Julien Faget |
| Author | Caroline Contat |
| Author | Nadine Zangger |
| Author | Solange Peters |
| Author | Etienne Meylan |
| Abstract | INTRODUCTION: NSCLC is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-?B (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy. METHODS: Receptor activator of NF-?B gene (RANK) and receptor activator of NF-?B 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. RESULTS: 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 KrasLSL-G12D/WT, KrasLSL-G12D/WT; Lkb1Flox/Flox and KrasLSL-G12D/WT; p53Flox/Flox 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. CONCLUSIONS: 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. |
| Publication | Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer |
| Volume | 13 |
| Issue | 3 |
| Pages | 387-398 |
| Date | 03 2018 |
| Journal Abbr | J Thorac Oncol |
| Language | eng |
| DOI | 10.1016/j.jtho.2017.11.121 |
| ISSN | 1556-1380 |
| Library Catalog | PubMed |
| Extra | PMID: 29223537 |
| Tags | Adenocarcinoma of Lung, Animals, Disease Models, Animal, first-last-corresponding, Genetic Engineering, Genetically engineered mouse models, Lung Neoplasms, Mice, original, Preclinical trial, RANK Ligand, Retrospective Studies, Signal Transduction |
| Date Added | 2019/05/28 - 21:19:23 |
| Date Modified | 2019/05/28 - 21:19:50 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
Institut de Recherche en Cancérologie de
