Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma
| العنوان: | Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma |
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| المؤلفون: | Pierpaolo Coluccia, Debora Malpicci, Maria Rosaria Torrisi, Emanuele Marra, Francesca Belleudi, Arianna Di Napoli, Giuseppe Roscilli, Rosa Camerlingo, Rita Mancini, Antoni Ribas, Luigi Fattore, Maria Elena Pisanu, Alessia Noto, Paolo A. Ascierto, Gennaro Ciliberto, Claudia De Vitis, Luigi Aurisicchio |
| المصدر: | Oncotarget, vol 6, iss 28 Oncotarget |
| بيانات النشر: | eScholarship, University of California, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Indoles, Receptor, ErbB-3, endocrine system diseases, MAP Kinase Kinase 1, Drug Resistance, braf/mek inhibitors, erbb3 activation, anti-erbb3 antibodies, in vivo regrowth impairment, melanoma, Epitope, Mice, Epitopes, ErbB-3, Antineoplastic Combined Chemotherapy Protocols, Monoclonal, ERBB3, Phosphorylation, skin and connective tissue diseases, Sulfonamides, Tumor, Blotting, Melanoma, Antibodies, Monoclonal, Drug Synergism, Oncology, ErbB3 activation, Neuregulin, Western, Research Paper, Receptor, Proto-Oncogene Proteins B-raf, BRAF/MEK inhibitors, Pyridones, Blotting, Western, Oncology and Carcinogenesis, Pyrimidinones, Anti-ErbB3 antibodies, Biology, Antibodies, Cell Line, Cell Line, Tumor, medicine, Animals, Humans, Protein kinase B, neoplasms, Protein Kinase Inhibitors, Oncogene, Cell growth, medicine.disease, Xenograft Model Antitumor Assays, digestive system diseases, Vemurafenib, Drug Resistance, Neoplasm, Mutation, Cancer research, Neoplasm, Proto-Oncogene Proteins c-akt |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8931db007d9c3e434ddeb43aaf64620f https://escholarship.org/uc/item/7hf2c5gq |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8931db007d9c3e434ddeb43aaf64620f |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |