Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression
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Chiara Ciardiello1,*, Maria Serena Roca1,*, Alessia Noto1, Francesca Bruzzese1, Tania Moccia1, Carlo Vitagliano1, Elena Di Gennaro1, Gennaro Ciliberto2, Giuseppe Roscilli3, Luigi Aurisicchio3, Emanuele Marra3, Rita Mancini4, Alfredo Budillon1, Alessandra Leone1
1Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy
2Scientific Direction, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy
3Takis s.r.l., University, 00161 Rome, Italy
4Department of Surgery "P.Valdoni” and Department of Clinical and Molecular Medicine, “La Sapienza” University, 00161 Rome, Italy
*These author contributed equally to this work
Alfredo Budillon, e-mail: [email protected]
Keywords: NSCLC, HDAC inhibitor, ErbB3, valproic acid, primary tumor cultures
Received: September 14, 2015 Accepted: January 23, 2016 Published: February 04, 2016
ErbB3, a member of the ErbB family receptors, has a key role in the development and progression of several cancers, including non-small cell lung cancer (NSCLC), and in the establishment of resistance to therapies, leading to the development of anti-ErbB3 therapies.
In this study we demonstrated, in a set of malignant pleural effusion-derived cultures of NSCLC, the synergistic antitumor effect of a histone deacetylase inhibitor (HDACi), such as vorinostat or valproic acid (VPA), in combination with the anti-ErbB3 monoclonal antibody (MoAb) A3. Synergistic interaction was observed in 2D and in 3D cultures conditions, both in fully epithelial cells expressing all ErbB receptors, and in cells that had undergone epithelial to mesenchymal transition and expressed low levels of ErbB3. We provided evidences suggesting that differential modulation of ErbB receptors by vorinostat or VPA, also at low doses corresponding to plasma levels easily reached in treated patients, is responsible for the observed synergism. In details, we showed in epithelial cells that both vorinostat and VPA induced time- and dose-dependent down-regulation of all three ErbB receptors and of downstream signaling. On the contrary, in A3-resistant mesenchymal cells, we observed time- and dose-dependent increase of mRNA and protein levels as well as surface expression of ErbB3, paralleled by down-regulation of EGFR and ErbB2. Our results suggest that the combination of a HDACi plus an anti-ErbB3 MoAb represents a viable strategy that warrants further evaluation for the treatment of NSCLC patients.
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