Dasatinib Inhibits the Development of Metastases in a Mouse Model of Pancreatic Ductal Adenocarcinoma

Jennifer P Morton, Saadia A Karim, Kathryn Graham, Paul Timpson, Nigel Jamieson, Dimitris Athineos, Brendan Doyle, Colin McKay, Man-Yeung Heung, Karin A Oien, Margaret C Frame, T R Jeffry Evans, Owen J Sansom, Valerie G Brunton

Research output: Contribution to journalArticlepeer-review

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 Trp53R172H and KrasG12D 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-KrasG12D/+, LSL-Trp53R172H/+ 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.
Original languageEnglish
Pages (from-to)292-303
Number of pages12
JournalGastroenterology
Volume139
Issue number1
DOIs
Publication statusPublished - Jul 2010

Keywords

  • Pancreatic Cancer
  • Metastasis
  • Src Kinase
  • Dasatinib

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