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

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 Antonio Ascierto, Rita Mancini, Gennaro Ciliberto

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)24823-24841
Number of pages19
JournalOncotarget
Volume6
Issue number28
DOIs
Publication statusPublished - 2015

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Keywords

  • Anti-ErbB3 antibodies
  • BRAF/MEK inhibitors
  • ErbB3 activation
  • In vivo regrowth impairment
  • Melanoma

ASJC Scopus subject areas

  • Oncology

Cite this

Fattore, L., Malpicci, D., Marra, E., Belleudi, F., Noto, A., Vitis, C. D., Pisanu, M. E., Coluccia, P., Camerlingo, R., Roscilli, G., Ribas, A., Napoli, A. D., Torrisi, M. R., Aurisicchio, L., Ascierto, P. A., Mancini, R., & Ciliberto, G. (2015). Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma. Oncotarget, 6(28), 24823-24841. https://doi.org/10.18632/oncotarget.4485