title: Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression.
abstract: 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.
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Chiara
authors: C
authors: Ciardiello
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Maria Serena
authors: MS
authors: Roca
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Alessia
authors: A
authors: Noto
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Francesca
authors: F
authors: Bruzzese
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Tania
authors: T
authors: Moccia
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Carlo
authors: C
authors: Vitagliano
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Elena
authors: E
authors: Di Gennaro
authors: Scientific Direction, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Gennaro
authors: G
authors: Ciliberto
authors: Takis s.r.l., University, 00161 Rome, Italy.
authors: Giuseppe
authors: G
authors: Roscilli
authors: Takis s.r.l., University, 00161 Rome, Italy.
authors: Luigi
authors: L
authors: Aurisicchio
authors: Takis s.r.l., University, 00161 Rome, Italy.
authors: Emanuele
authors: E
authors: Marra
authors: Department of Surgery "P.Valdoni" and Department of Clinical and Molecular Medicine, "La Sapienza" University, 00161 Rome, Italy.
authors: Rita
authors: R
authors: Mancini
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Alfredo
authors: A
authors: Budillon
authors: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
authors: Alessandra
authors: A
authors: Leone
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000911:Antibodies, Monoclonal; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D014635:Valproic Acid; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: ErbB3; HDAC inhibitor; NSCLC; primary tumor cultures; valproic acid