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An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling

Oncogene volume 31, pages 1275–1286 (2012)Cite this article

Abstract

The ErbB receptors, such as ErbB-1 and ErbB-2, have been intensely pursued as targets for cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance, which is often associated with reactivation of the ErbB-3-PI3K-Akt signaling. This may be overcome by an ErbB-3 ligand that abrogates receptor-mediated signaling. Toward this end, we have generated a mouse monoclonal antibody, MP-RM-1, against the extracellular domain (ECD) of ErbB-3 receptor. Assessment of human tumor cell lines, as well as early passage tumor cells revealed that MP-RM-1 effectively inhibited both NRG-1β-dependent and -independent ErbB-3 activation. The antagonizing effect of MP-RM-1 was of non-competitive type, as binding of [125I]-labeled NRG-1β to ErbB-3 was not influenced by the antibody. MP-RM-1 treatment led, in most instances, to decreased ErbB-3 expression. In addition, MP-RM-1 was able to inhibit the colony formation ability of tumor cells and tumor growth in two human tumor xenograft nude mouse models. Treatment with the antibody was associated with a decreased ErbB-3 and Akt phosphorylation and ErbB-3 expression in the excised tumor tissue. Collectively, these results indicate that MP-RM-1 has the potential to interfere with signaling by ErbB-3 and reinforce the notion that ErbB-3 could be a key target in cancer-drug design.

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Acknowledgements

We thank Dr F Petronzelli (Sigma-Tau Pomezia, Italy) for the measurement of MP-RM-1 affinity by surface plasmonic resonance; Dr O Segatto, Dr S Anastasi and Dr M Sallese for advice and reagents, R La Sorda and MR Nicotra for the immunohistochemical analysis, Dr A Sala and Professor V De Laurenzi for discussion. PGN and MP partially supported by AIRC.

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  1. MediaPharma s.r.l., Chieti, Italy

    G Sala, S Traini, M D'Egidio, E Piccolo, M Piantelli, N Tinari, P G Natali, R Muraro & S Iacobelli

  2. Departement of Oncology and Experimental Medicine, University Foundation ‘G. D’Annunzio’ Chieti-Pescara, Chieti, Italy

    G Sala, S Traini, M D'Egidio, G Vianale, C Rossi, E Piccolo, R Lattanzio, M Piantelli, N Tinari, R Muraro & S Iacobelli

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Sala, G., Traini, S., D'Egidio, M. et al. An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling. Oncogene 31, 1275–1286 (2012). https://doi.org/10.1038/onc.2011.322

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