title: Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis.
abstract: Purpose:AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design:We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated withAXLexpression are enriched in EMT, migration, and invasion signaling pathways.Results:Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion.In vitrostimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, andVIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions:The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation.Clin Cancer Res; 23(11); 2806-16. ©2016 AACR.
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Wilhem
authors.initials: W
authors.lastname: Leconet
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Chentouf
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: du Manoir
authors.affiliation: CNRS UMR5237, University of Montpellier, CRBM, Montpellier, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Chevalier
authors.affiliation: CNRS UMR5237, University of Montpellier, CRBM, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sirvent
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Imade
authors.initials: I
authors.lastname: Aït-Arsa
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Busson
authors.affiliation: Unité de Biométrie, ICM, Montpellier, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Jarlier
authors.affiliation: Department of Biopathology, The Jean Perrin Comprehensive Cancer Center and ERTICa Research Group, University of Auvergne, Clermont-Ferrand, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Radosevic-Robin
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Theillet
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Dany
authors.initials: D
authors.lastname: Chalbos
authors.affiliation: INSERM-U876, Hématopoïèse Leucémique et Cible Thérapeutique, Université Victor Ségalen, Laboratoire d'hématologie CHU de Bordeaux, Bordeaux, Cedex, France.
authors.forename: Jean-Max
authors.initials: JM
authors.lastname: Pasquet
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: André
authors.initials: A
authors.lastname: Pèlegrin
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Larbouret
authors.affiliation: IRCM-INSERM-U1194, Université de Montpellier, ICM, Montpellier, France. bruno.robert@inserm.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Robert
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage* / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000888:Antibodies, Anti-Idiotypic; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase