BACKGROUND: Pancreatic cancer is a devastating and highly aggressive disease with a mortality rate >95%. Current therapeutics for pancreatic cancer are failing and there is an increasing need for more effective agents. We developed a novel class of anti-tumour agents, namely Dp44mT and DpC, which have shown potent anti-cancer activity against aggressive pancreatic cancer in vitro and in vivo. Notably, our lead agent DpC has entered clinical trials in 2016 further highlighting its potential. The activity of these agents is, at least in part, mediated by their ability to up-regulate the potent growth and metastasis suppressor, N-myc down-stream regulated gene 1 (NDRG1). NDRG1 inhibits cell proliferation, migration and invasion by negatively regulating numerous oncogenic-signalling pathways. However, the mechanisms by which NDRG1 modulates all these pathways remain to be elucidated.
AIMS: To examine how NDRG1, Dp44mT and DpC affects multiple signalling pathways, we assessed their effects on the ErbB-family of receptor tyrosine kinases, namely EGFR, HER2 and HER3, as these molecules are key regulators of oncogenic-signalling in pancreatic cancer.
METHODS: PANC1 and CFPAC-1 pancreatic cancer cells were utilized to examine the effects of NDRG1, Dp44mT and DpC on EGFR, HER2 and HER3 levels, localization and phosphorylation in vitro. PANC1 xenografts were utilized to examine the effects of Dp44mT and DpC on these molecules in vivo.
RESULTS: For the first time, we demonstrate that NDRG1, Dp44mT and DpC markedly inhibit the expression, localization, dimerization and activation of EGFR, HER2 and HER3. NDRG1 also reduced activation of the MAPK-signalling pathway, which is down-stream of the ErbB family of receptors. Further, both Dp44mT and DpC significantly reduced expression of EGFR, HER2 and HER3 in vivo.
CONCLUSION: This study demonstrates for the first time that Dp44mT and DpC, inhibit the ErbB family of proteins, providing a novel insight into the mechanisms behind their compelling anti-cancer activity and potential against pancreatic cancer.
Publication: Kovacevic Z., Menezes S.V., Sahni S., Kalinowski D.S., Bae D.H., Lane D.J. and Richardson D.R. (2016) The Metastasis Suppressor, N-myc Downstream Regulated Gene-1 (NDRG1), Down-Regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways. J Biol Chem. 291(3):1029-52.