Abstract 2846: Exploring ERBB3 as novel drug target in lung cancer

Abstract

Abstract Recent evidences point to ERBB3 as a critical activator of the PI3K/Akt signaling axis and suggest that its trans-phosphorylation is linked to the occurrence of drug resistance in several cancers. Because of the absence of a functional tyrosine kinase, the best approach to target this receptor is through the development of selective monoclonal antibodies. For this purpose, our group has recently generated a set of mouse monoclonals with low nM affinity for human ERBB3. We have started to assess the effect of these antibodies in lung cancer using two systems: a) PC9 cells, known to be highly sensitive to gefitinib (IC50 0,03 uM), for the DelE746A750 in exon 19 of EGFR and its gefitinib-resistant counterpart PC9-ZD (Koizumi et al, 2005 Int J. Cancer 116, 36); b) primary lung adenocarcinoma cells isolated in our laboratory from Malignant Pleural Effusions (MPEs) and capable of efficient tumor propagation in vivo (Mancini et al, 2011, PlosONE 6: e21320). In PC9 cells anti-ERBB3 mabs, A3 and A4, strongly inhibit ligand-induced pHER3 and pAKT and induce receptor downmodulation. Furthermore, A3 and A4 potentiate the antiproliferative effect of gefitinib in a clonogenic assay, induce G0/G1 arrest, and increase the percentage of cells that undergo apoptosis. In the human primary MPE-derived lung adenocarcinoma culture PEd10, we observed that the expression of ERBB3 and its ligand are upregulated when cells are grown in spheroid vs adherent conditions. In this system, A3 and A4 antibodies significantly downmodulate spheroid propagation. Studies are ongoing to provide further insights as to the mechanism of action of anti-ERBB3 antibodies and to confirm efficacy in in vivo tumor models. Our results suggest that in a subset of lung adenocarcinomas which express high levels of ERBB3, this receptor contributes to cell growth and propagation and that targeting ERBB3 with antibodies capable of inducing receptor downmodulation can be considered a promising therapeutic approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2846. doi:1538-7445.AM2012-2846