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Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma

2015; Impact Journals LLC; Volume: 6; Issue: 28 Linguagem: Inglês

10.18632/oncotarget.4485

1949-2553

Luigi Fattore, Debora Malpicci, Emanuele Marra, Francesca Belleudi, Alessia Noto, Claudia De Vitis, Maria Elena Pisanu, Pierpaolo Coluccia, Rosa Camerlingo, Giuseppe Roscilli, Antoni Ribas, Arianna Di Napoli, Maria Rosaria Torrisi, Luigi Aurisicchio, Paolo A. Ascierto, Rita Mancini, Gennaro Ciliberto,

HER2/EGFR in Cancer Research

// Luigi Fattore 1, 2 , Debora Malpicci 2, 3 , Emanuele Marra 4 , Francesca Belleudi 5, 6 , Alessia Noto 1, 2 , Claudia De Vitis 2, 5 , Maria Elena Pisanu 2, 3 , Pierpaolo Coluccia 2 , Rosa Camerlingo 1 , Giuseppe Roscilli 4, 5 , Antoni Ribas 7 , Arianna Di Napoli 5, 8 , Maria Rosaria Torrisi 5, 6, 8 , Luigi Aurisicchio 4 , Paolo Antonio Ascierto 1 , Rita Mancini 2, 5 , Gennaro Ciliberto 1 1 Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples, Italy 2 Dipartimento di Chirurgia "P. Valdoni", Sapienza Università di Roma, Rome, Italy 3 Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Catanzaro "Magna Graecia", Catanzaro, Italy 4 Takis S.r.l., Rome, Italy 5 Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy 6 Istituto Pasteur Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy 7 Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA 8 Azienda Ospedaliera S. Andrea, Rome, Italy Correspondence to: Gennaro Ciliberto, e-mail: g.ciliberto@istitutotumori.na.it Keywords: melanoma, BRAF/MEK inhibitors, ErbB3 activation, Anti-ErbB3 antibodies, in vivo regrowth impairment Received: March 16, 2015 Accepted: June 27, 2015 Published: July 07, 2015 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.