title: Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma.
abstract: Patients with metastatic melanoma bearing V600 mutations in BRAF oncogene clinically benefit from the treatment with BRAF inhibitors alone or in combination with MEK inhibitors. However, a limitation to such treatment is the occurrence of resistance. Tackling the adaptive changes helping cells survive from drug treatment may offer new therapeutic opportunities. Very recently the ErbB3 receptor has been shown to act as a central node promoting survival of BRAF mutated melanoma. In this paper we first demonstrate that ErbB3/AKT hyperphosphorylation occurs in BRAF mutated melanoma cell lines following exposure to BRAF and/or MEK inhibitors. This strongly correlates with increased transcriptional activation of its ligand neuregulin. Anti-ErbB3 antibodies impair the establishment of de novo cell resistance to BRAF inhibition in vitro. In order to more potently ablate ErbB3 activity we used a combination of two anti-ErbB3 antibodies directed against distinct epitopes of its extracellular domain. These two antibodies in combo with BRAF/MEK inhibitors potently inhibit in vitro cell growth and tumor regrowth after drug withdrawal in an in vivo xenograft model. Importantly, residual tumor masses from mice treated by the antibodies and BRAF/ERK inhibitors combo are characterized almost exclusively by large necrotic areas with limited residual areas of tumor growth. Taken together, our findings support the concept that triple therapy directed against BRAF/MEK/ErbB3 may be able to provide durable control of BRAF mutated metastatic melanoma.
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples, Italy.|Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Fattore
authors.affiliation: Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy.|Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Catanzaro "Magna Graecia", Catanzaro, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Malpicci
authors.affiliation: Takis S.r.l., Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Marra
authors.affiliation: Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.|Istituto Pasteur Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Belleudi
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples, Italy.|Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Noto
authors.affiliation: Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy.|Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: De Vitis
authors.affiliation: Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy.|Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Catanzaro "Magna Graecia", Catanzaro, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Pisanu
authors.affiliation: Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Coluccia
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Camerlingo
authors.affiliation: Takis S.r.l., Rome, Italy.|Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Roscilli
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.|Azienda Ospedaliera S. Andrea, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Di Napoli
authors.affiliation: Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.|Istituto Pasteur Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.|Azienda Ospedaliera S. Andrea, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Torrisi
authors.affiliation: Takis S.r.l., Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Aurisicchio
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples, Italy.
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy.|Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Mancini
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D020893:Receptor, ErbB-3; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1
keywords: Anti-ErbB3 antibodies; BRAF/MEK inhibitors; ErbB3 activation; in vivo regrowth impairment; melanoma