Abstract 2009: Histone deacetylase inhibitors (HDI) down-regulate Ron kinase and synergize with Ron knockdown or Ron monoclonal antibody 41A10to treat pancreatic cancer

Abstract Receptor tyrosine kinase Ron (recepteur d'origine nantais) has been reported to be overexpressed in a panel of pancreatic cancer cells, as well as in tissue samples from pancreatic cancer patients and has been correlated to late stages of pancreatic cancer. Here we hypothesize that Ron kinase can be served as a potential therapeutic target. Our study showed that Ron-specific shRNA significantly altered oncogenic signaling as reflected by reduced pRon, pAkt and pERK in conjunction with reduced cell motility, as evidenced by wound healing assays and transwell assays. Ron knockdown also reduced HIF1α expression. HIF1α is constitutively expressed in many pancreatic cancer cells and has been reported to be a transcription factor for Ron and CXCR4 gene expression, indicating the reciprocal control for these two proteins. Targeting HIF1α and Ron may represent a novel therapeutic strategy for Ron-overexpressing pancreatic cancer patients. Histone deacetylase (HDAC) inhibitors have been reported to target HIF1α gene expression and alter the interaction of HSP70/90 with their client proteins through disruption of HSP70/HSP90 by HDAC6. We demonstrate here that HDAC inhibitors TSA and Panobinostat significantly reduced HIF1α, Ron kinase and CXCR4 expression in pancreatic cancer cells, which was associated with attenuation of pAkt and pERK. Thus our work indicates that HDAC inhibitor therapy targets both Ron and HIF1α. Our future work will demonstrate that Panobinostat can synergize with Ron knockdown or Ron monoclonal antibody to reduce cell growth by colony formation assay. Molecular mechanism will also be investigated. Ron, HIF1α and CXCR4 were reported to increase tumor metastasis. Whether HDI such as Panobinostat alone or in combination with Ron knockdown or Ron monoclonal antibody can reduce metastasis through downregulation of these metastasis related genes will be further investigated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2009. doi:10.1158/1538-7445.AM2011-2009