Abstract A63: Role of the metastasis suppressor, NDRG1, in regulating the EGFR and ErbB family of receptors and its effects on key oncogenic signaling pathways in pancreatic cancer

Abstract

Abstract N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that has been shown to affect numerous signaling pathways that control oncogenesis. In this study, the role of NDRG1 was investigated on a key upstream effector, namely epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor 2 (HER2) and human epidermal growth factor receptor 3 (HER3). This is of interest, as the ErbB family of receptor tyrosine kinases are involved in regulating multiple cell responses, being key regulators of down-stream oncogenic-signaling. We demonstrate that NDRG1 is able to significantly reduce the expression, localisation and activation of EGFR, HER2 and HER3, while also inhibiting the formation of EGFR/HER2 and HER2/HER3 heterodimers. This investigation also showed that a novel class of anti-cancer agents, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), were able to markedly up-regulate NDRG1. These agents were found to inhibit EGFR, HER2 and HER3 expression and phosphorylation in PANC-1 pancreatic cancer cells in vitro. Moreover, these compounds led to a significant reduction of the expression of these proteins in PANC-1 tumour xenografts in vivo. Due to the limitations of current anti-cancer therapeutics, these agents were also compared to a clinically used EGFR inhibitor, Erlotinib. Our study showed that in comparison to Erlotinib, both Dp44mT and DpC displayed higher anti-proliferative activity in pancreatic cancer cells. This could be significant, as DpC is due to enter clinical trials this year for the treatment of aggressive solid tumours (http://www.colmeddev.com/oncochel/). Together, these findings reveal the molecular mechanisms that underlie the anti-cancer effects of NDRG1, and in turn, demonstrate the potential origin of the extensive down-stream effects attributed to this molecule. Citation Format: Sharleen V. Menezes, Zaklina Kovacevic, Des R. Richardson. Role of the metastasis suppressor, NDRG1, in regulating the EGFR and ErbB family of receptors and its effects on key oncogenic signaling pathways in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A63.