Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma.

Abstract

BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and metastatic disease for which conventional treatments are of limited efficacy. A number of agents in development are potential anti-invasive and antimetastatic agents, including the Src kinase inhibitor dasatinib. The aim of this study was to assess the importance of Src in human PDAC and to use a genetically engineered mouse model of PDAC to determine the effects of dasatinib on PDAC progression. METHODS Src expression and activity was measured by immunohistochemistry in 114 human PDACs. Targeting expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas results in the formation of invasive and metastatic PDAC. These mice were treated with dasatinib, and disease progression monitored. Cell lines were derived from mouse PDACs, and in vitro effects of dasatinib assessed. RESULTS Src expression and activity were up-regulated in human PDAC and this correlated with reduced survival. Dasatinib inhibited the migration and invasion of PDAC cell lines, although no effects on proliferation were seen at concentrations that inhibited Src kinase activity. In addition, dasatinib significantly inhibited the development of metastases in Pdx1-Cre, Z/EGFP, LSL-Kras(G12D/+), LSL-Trp53(R172H/+) mice. However, there was no survival advantage in the dasatinib-treated animals owing to continued growth of the primary tumor. CONCLUSIONS This study confirms the importance of Src in human PDAC and shows the usefulness of a genetically engineered mouse model of PDAC for assessing the activity of potential antimetastatic agents and suggests that dasatinib should be evaluated further as monotherapy after resection of localized invasive PDAC.

DOI: 10.1053/j.gastro.2010.03.034
02040602011201220132014201520162017
Citations per Year

168 Citations

Semantic Scholar estimates that this publication has 168 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Morton2010DasatinibIT, title={Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma.}, author={Jennifer P Morton and Saadia A Karim and Kathryn Graham and Paul Timpson and Nigel Jamieson and Dimitris Athineos and Brendan Doyle and Colin McKay and Man-Yeung Heung and Karin A Oien and Margaret C Frame and T R Jeffry Evans and Owen J Sansom and Valerie G Brunton}, journal={Gastroenterology}, year={2010}, volume={139 1}, pages={292-303} }