Abstract 5444: Modulation of ErbB receptors expression by histone deacetylase inhibitors increased the antitumor activity of an anti-ErbB3 monoclonal antibody in primary cultures from non-small cell lung cancer patients
Authors: Ciardiello Chiara , Leone Alessandra , Bruzzese Francesca , Roca Maria Serena , Noto Alessia , Vitis Claudia D. , Aurisicchio Luigi , Ciliberto Gennaro , Mancini Rita , Budillon Alfredo 
Published: May 2015

Abstract
In the last years several evidences suggested that ErbB3, a member of the HER family receptors, has a key role in the development and progression of several cancers including non-small cell lung cancer (NSCLC), and above all in the establishment of resistance to therapies, leading to major efforts towards the development of anti-ErbB3 therapies. We recently demonstrated in head and neck cancer cells that, depending on the ErbB3 expression level and on the tumor cell phenotype (epithelial vs mesenchymal), vorinostat, one of the two clinically approved histone deacetylase inhibitors (HDACi), differentially regulates HER receptors expression at the transcriptional level and/or by modulating protein degradation (Bruzzese F. et al. J Cell Physiol. 2011; 226(9):2378-90). Our group has developed a monoclonal antibody against ErbB3 called A3, that induces receptor internalization and degradation, inhibits growth and induces apoptosis only in cells overexpressing surface ErbB3 and potentiates the efficacy of EGFR TKIs (Noto A. et al. Oncotarget. 2013; 4(8):1253-65).
In this study we first show, by using a set of malignant pleural effusion derived cell cultures from NSCLC patients (Mancini R. et al. PLOSone 2011; 6(7):e21320) that the combination of the anti-ErbB3 antibody A3 with HDACi such as vorinostat or valproic acid (VPA), synergistically affect cell proliferation and induce apoptosis. Interestingly synergistic interaction was observed in both fully epithelial cells expressing all HER receptors including ErbB3, as well as in NSCLC cells that had undergone EMT and expressed very low levels of ErbB3. We provide evidences suggesting that differential modulation of ErbB receptors by HDACi is responsible for the observed synergism. We show in two epithelial cells expressing EGFR, ErbB2, and ErbB3 that either vorinostat or VPA time- and dose-dependent down-regulation the of all three receptors expression and signaling. On the contrary, in two A3-resistant mesenchymal cells expressing undetectable levels of ErbB3, we observe time- and dose-dependent increase of mRNA and protein levels as well as surface expression of ErbB3, paralleled by down-regulation of EGFR, ErbB2 and the the mesenchymal marker vimentin. Interestingly, ErbB3 induction was achieved also at low doses of both vorinostat and VPA, corresponding to a plasma level easily reached in patients treated with these agents.
Our results suggest that the combination treatment of antibodies against ErbB3 and HDACi represents an attractive strategy that warrant further evaluation, even in combination with other agents, for the treatment of NSCLC patients.
Citation Format: Chiara Ciardiello, Alessandra Leone, Francesca Bruzzese, Maria Serena Roca, Alessia Noto, Claudia De Vitis, Luigi Aurisicchio, Gennaro Ciliberto, Rita Mancini, Alfredo Budillon. Modulation of ErbB receptors expression by histone deacetylase inhibitors increased the antitumor activity of an anti-ErbB3 monoclonal antibody in primary cultures from non-small cell lung cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5444. doi:10.1158/1538-7445.AM2014-5444