Ciardiello Chiara, Roca Maria Serena, Noto Alessia, Bruzzese Francesca, Moccia Tania, Vitagliano Carlo, Di Gennaro Elena, Ciliberto Gennaro, Roscilli Giuseppe, Aurisicchio Luigi, Marra Emanuele, Mancini Rita, Budillon Alfredo, Leone Alessandra
Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
Scientific Direction, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, 80131 Naples, Italy.
Oncotarget. 2016 Apr 12;7(15):19559-74. doi: 10.18632/oncotarget.7195.
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.
ErbB3是ErbB家族受体成员之一，在包括非小细胞肺癌（NSCLC）在内的多种癌症的发生和发展以及耐药性的形成中起关键作用，从而促使了抗ErbB3疗法的研发。在本研究中，我们在一组源自NSCLC恶性胸腔积液的培养物中证明，组蛋白去乙酰化酶抑制剂（HDACi），如伏立诺他或丙戊酸（VPA），与抗ErbB3单克隆抗体（MoAb）A3联合使用具有协同抗肿瘤作用。在二维和三维培养条件下，在表达所有ErbB受体的完全上皮细胞以及经历上皮-间质转化并表达低水平ErbB3的细胞中均观察到协同相互作用。我们提供的证据表明，伏立诺他或VPA对ErbB受体的差异调节，即使在与治疗患者易于达到的血浆水平相对应的低剂量下，也是观察到的协同作用的原因。具体而言，我们在上皮细胞中表明，伏立诺他和VPA均诱导所有三种ErbB受体及其下游信号传导的时间和剂量依赖性下调。相反，在对A3耐药的间充质细胞中，我们观察到ErbB3的mRNA和蛋白水平以及表面表达呈时间和剂量依赖性增加，同时伴有EGFR和ErbB2的下调。我们的结果表明，HDACi与抗ErbB3 MoAb的联合使用是一种可行的策略，值得进一步评估用于治疗NSCLC患者。
