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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.

SUBMITTER: Ciardiello C

PROVIDER: S-EPMC4991401 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression.

Ciardiello Chiara C Roca Maria Serena MS Noto Alessia A Bruzzese Francesca F Moccia Tania T Vitagliano Carlo C Di Gennaro Elena E Ciliberto Gennaro G Roscilli Giuseppe G Aurisicchio Luigi L Marra Emanuele E Mancini Rita R Budillon Alfredo A Leone Alessandra A

Oncotarget 20160401 15

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 wi ...[more]

PMID: 26862736

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Project description:Background: Studies have shown that the expression of histone deacetylases (HDACs) is significantly related to the tumor microenvironment (TME) in gastric cancer. However, the expression of a single molecule or several molecules does not accurately reflect the TME characteristics or guide immunotherapy in gastric cancer. Methods: We constructed an HDAC score (HDS) based on the expression level of HDACs. The single-cell transcriptome was used to analyze the underlying factors contributing to differences in immune infiltration between patients with a high and low HDS. In vitro and in vivo experiments validated the strategy of transforming cold tumors into hot tumors to guide immunotherapy. Results: According to the expression characteristics of HDACs, we constructed an HDS model to characterize the TME. We found that patients with a high HDS had stronger immunogenicity and could benefit more from immunotherapy than those with a low score. The AUC value of the HDS combined with the combined positive score (CPS)for predicting the efficacy of immunotherapy was as high as 0.96. By single-cell and paired bulk transcriptome sequencing analysis, we found that the infiltration levels of CD4+ T cells, CD8+ T cells and NK cells were significantly decreased in the low HDS group, which may be induced by MYH11+ fibroblasts, CD234+ endothelial cells and CCL17+ pDCs via the MIF signaling pathway. Inhibition of the MIF signaling pathway was confirmed to potentially enhance immune infiltration. In addition, our analysis revealed that GPX4 inhibitors might be effective for patients with a low HDS. GPX4 knockout significantly inhibited PD-L1 expression and promoted the infiltration and activation of CD8+ T cells. Conclusion: We constructed an HDS model based on the HDAC expression characteristics of gastric cancer. This model was used to evaluate TME characteristics and predict immunotherapy efficacy. Inhibition of the MIF signaling pathway in the TME and GPX4 expression in tumor cells may be an important strategy for cold tumor synergistic immunotherapy for gastric cancer.

Dataset Information

Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression.

Publications

Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression.

Similar Datasets

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