Abstract A165: Novel thiosemicarbazone, Dp44mT, promotes NDRG1 to downregulate oncogenic signaling pathways in cancer

Abstract

Abstract Introduction: The novel thiosemicarbazone, Dp44mT, has shown potent anticancer activity against various cancer types. The activity of this agent is, at least in part, mediated by its ability to upregulate the growth and metastasis suppressor, N-myc Downstream Regulated Gene 1 (NDRG1). NDRG1 inhibits cell proliferation, migration, and invasion by negatively regulating numerous oncogenic signaling pathways. However, the mechanisms by which NDRG1 modulates all these pathways remain to be elucidated. To examine how NDRG1 and Dp44mT affect multiple signalling pathways, we assessed their effects on the ErbB-family of receptor tyrosine kinases, namely epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), as these molecules are key regulators of downstream oncogenic signaling. Methods: PANC1 pancreatic and HT-29 colon human cancer cells were utilized to examine the effects of NDRG1 and Dp44mT on EGFR, HER2, and HER3 levels, localization, and phosphorylation in vitro. PANC1 xenografts were also utilized to examine the effects of Dp44mT on these molecules in vivo. Results: For the first time, we demonstrate that NDRG1 and Dp44mT markedly inhibit the expression, localization, and activation of EGFR, HER2, and HER3. NDRG1 also reduced activation of the MAPK-signalling pathway, which is downstream of the ErbB family of receptors. Further, the anticancer agent, Dp44mT, significantly reduced expression of EGFR, HER2, and HER3 in vivo. Conclusions: This study demonstrates for the first time that the novel thiosemicarbazone, Dp44mT, inhibits the ErbB family of proteins through its upregulation of NDRG1, providing an interesting insight into the mechanisms behind its compelling anticancer activity. Citation Format: Sharleen V. Menezes, Zaklina Kovacevic, Des Richardson. Novel thiosemicarbazone, Dp44mT, promotes NDRG1 to downregulate oncogenic signaling pathways in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A165.