title: Dual inhibition using cabozantinib overcomes HGF/MET signaling mediated resistance to pan-VEGFR inhibition in orthotopic and metastatic neuroblastoma tumors.
abstract: MET is expressed on neuroblastoma cells and may trigger tumor growth, neoangiogenesis and metastasis. MET upregulation further represents an escape mechanism to various anticancer treatments including VEGF signaling inhibitors. We developed in vitro a resistance model to pan-VEGFR inhibition and explored the simultaneous inhibition of VEGFR and MET in neuroblastoma models in vitro and in vivo using cabozantinib, an inhibitor of the tyrosine kinases including VEGFR2, MET, AXL and RET. Resistance in IGR-N91-Luc neuroblastoma cells under continuous in vitro exposure pressure to VEGFR1-3 inhibition using axitinib was associated with HGF and p-ERK overexpression. Cabozantinib exhibited anti-proliferative effects in neuroblastoma cells and reduced cell migration in vitro as measured by phase-contrast with IncuCyte system. In vivo, an enhanced number of animals with IGR-N91-Luc metastases was noted following axitinib treatment as compared to control animals. Orally administered cabozantinib per gavage at 30 and 60 mg/kg/day significantly inhibited tumor growth of orthotopic adrenal IGR-N91-Luc and metastatic IMR-32-Luc xenografts. Antitumor activity was associated with decreased vascularization, inhibition of p-SRC and induction of apoptotic cell death. Activation of the HGF-mediated MET pathway is involved in escape to selective VEGFR inhibition in neuroblastoma suggesting combined inhibition of MET and VEGFR signaling to reduce secondary resistance and enhanced invasiveness.
authors.affiliation: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Univ. Paris-Sud, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos-Dubus
authors.affiliation: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Univ. Paris-Sud, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Le Dret
authors.affiliation: Preclinical Evaluation Platform, Gustave Roussy, Villejuif, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Bawa
authors.affiliation: Preclinical Evaluation Platform, Gustave Roussy, Villejuif, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.affiliation: Tribvn, Châtillon, France.
authors.forename: Albane
authors.initials: A
authors.lastname: Vievard
authors.affiliation: Pathology Laboratory, Gustave Roussy, Villejuif, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Villa
authors.affiliation: Pathology Laboratory, Gustave Roussy, Villejuif, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bosq
authors.affiliation: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Univ. Paris-Sud, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.affiliation: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Univ. Paris-Sud, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
mesh_terms: D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077784:Axitinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007191:Indazoles / Q000008:administration & dosage; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; C066855:HGF protein, human; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C558660:cabozantinib; D017228:Hepatocyte Growth Factor; D000077784:Axitinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040281:Vascular Endothelial Growth Factor Receptor-1; D048049:Extracellular Signal-Regulated MAP Kinases