Julien Faget1, Caroline Contat1, Nadine Zangger2, Solange Peters3, Etienne Meylan4. 1. Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 2. Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland. 3. Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. 4. Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Electronic address: etienne.meylan@epfl.ch.
Abstract
INTRODUCTION: 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. METHODS: 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. 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.
INTRODUCTION: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. METHODS: Receptor activator of NF-κB gene (RANK) and receptor activator of NF-κB ligand gene (RANKL) expression in humanlung 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 humanlung 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.
Authors: Christine Hjorth Andreassen; Mette Lorenzen; John E Nielsen; Sam Kafai Yahyavi; Birgitte Grønkær Toft; Lars R Ingerslev; Christoffer Clemmensen; Lene Juel Rasmussen; Carsten Bokemeyer; Anders Juul; Anne Jørgensen; Martin Blomberg Jensen Journal: Br J Cancer Date: 2022-04-13 Impact factor: 9.075
Authors: Amaia Martinez-Usatorre; Ece Kadioglu; Gael Boivin; Chiara Cianciaruso; Alan Guichard; Bruno Torchia; Nadine Zangger; Sina Nassiri; Ioanna Keklikoglou; Martina Schmittnaegel; Carola H Ries; Etienne Meylan; Michele De Palma Journal: Sci Transl Med Date: 2021-08-11 Impact factor: 17.956
Authors: Peter A van Dam; Yannick Verhoeven; Julie Jacobs; An Wouters; Wiebren Tjalma; Filip Lardon; Tim Van den Wyngaert; Jonatan Dewulf; Evelien Smits; Cécile Colpaert; Hans Prenen; Marc Peeters; Martin Lammens; Xuan Bich Trinh Journal: Int J Mol Sci Date: 2019-05-02 Impact factor: 5.923