Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts

BMC Cancer

Research Article

Qing Chang¹  David W Hedley²  Jeffrey N Miner³  Mark S Chapman³ 

[1] Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada;Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada;Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada;Research and Development, Ardea Biosciences, Inc., 4939 Directors Place, San Diego, CA, USA;

关键词: Pancreatic Cancer;    Rapamycin;    Pancreatic Cancer Cell Line;    Oral Gavage;    Significant Growth Inhibition;   

DOI  :  10.1186/1471-2407-10-515

 received in 2010-06-17, accepted in 2010-09-28,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCombining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically.MethodsAnti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation in vivo.ResultsRDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved in vivo are similar to those that produce target inhibition and cell cycle arrest in vitro.ConclusionsAgents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.

【 授权许可】

Unknown   
© Chang et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.