title: VEGF blockade enhances the antitumor effect of BRAFV600E inhibition.
abstract: The development of resistance remains a major obstacle to long-term disease control in cancer patients treated with targeted therapies. In BRAF-mutant mouse models, we demonstrate that although targeted inhibition of either BRAF or VEGF initially suppresses the growth of BRAF-mutant tumors, combined inhibition of both pathways results in apoptosis, long-lasting tumor responses, reduction in lung colonization, and delayed onset of acquired resistance to the BRAF inhibitor PLX4720. As well as inducing tumor vascular normalization and ameliorating hypoxia, this approach induces remodeling of the extracellular matrix, infiltration of macrophages with an M1-like phenotype, and reduction in cancer-associated fibroblasts. At the molecular level, this therapeutic regimen results in a de novo transcriptional signature, which sustains and explains the observed efficacy with regard to cancer progression. Collectively, our findings offer new biological rationales for the management of clinical resistance to BRAF inhibitors based on the combination between BRAFV600Einhibitors with anti-angiogenic regimens.
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Comunanza
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute IRCCS, Candiolo, Italy.|Center for Molecular Systems Biology, University of Torino, Orbassano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Corà
authors.affiliation: Center for Molecular Systems Biology, University of Torino, Orbassano, Italy.|Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Orso
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Consonni
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Middonti
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Federica
authors.identifier: 0000-0001-9618-2010
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Buzdin
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, Italy.|Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sica
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Enzo
authors.identifier: 0000-0002-3917-2438
authors.initials: E
authors.lastname: Medico
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute IRCCS, Candiolo, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Sangiolo
authors.affiliation: Center for Molecular Systems Biology, University of Torino, Orbassano, Italy.|Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Taverna
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy federico.bussolino@unito.it.|Candiolo Cancer Institute IRCCS, Candiolo, Italy.|Center for Molecular Systems Biology, University of Torino, Orbassano, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D050505:Mutant Proteins; C528407:PLX 4720; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
keywords: angiogenesis; drug resistance; extracellular matrix; myeloid infiltration; vascular normalization