Abstract #LB-217: Dasatinib inhibits the development of metastases in a mouse model of pancreatic cancer
Authors: Thomas Evans, Jennifer Morton, Saadia Karim, Dimitris Athineos, Margaret Frame, Owen Sansom, Valerie Brunton
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Pancreatic ductal adenocarcinoma (PDAC) is characterised by aggressive invasion, early metastases, and poor survival. 90% of patients have surgically unresectable disease at presentation, and the majority of the selected patients who undergo potentially curative resection for small, localised lesions inevitably develop recurrent or metastatic disease, presumably due to the presence of distant micro-metastases at initial diagnosis. Src family kinases (SFKs) play an important role in tumor cell adhesion, migration and invasion, and in the development of metastases. We evaluated whether dasatinib, an inhibitor of several kinases including SFKs and BCR-ABL, can inhibit the development of metastases in a mouse model of PDAC. Targeting endogenous expression of Trp53R172H and KrasG12D to the mouse pancreas, via the Pdx1 pancreaticprogenitor cell gene promoter, results in the formation of pre-invasivepancreatic intraepithelial neoplasia (PanIN) which developsinto invasive and metastatic pancreatic cancer which mimics the biologic and clinical features of the human disease, with PanIN by 6 weeks of age and non-metastatic malignant disease burden apparent inanimals by 10 weeks of age. Src activity and expression was low in normal pancreatic ducts and in early PanIN lesions from these mice but was markedly increased in PanIN-3 and PDAC as determined by pSrctyr418 immunohistochemistry and Western blotting. Using 3 cell lines derived from mouse PDAC, dasatinib (100 - 200 nM) resulted in a dose-dependent inhibition of Src kinase activity, as determined by pSrctyr418 levels. Dasatinib, at a Src kinase-inhibitory dose, inhibited mouse PDAC cell migration (wound assay) but not proliferation of mouse PDAC cells in vitro , although 25-40% inhibition of proliferation was observed at higher concentrations (1uM). Pdx1-Cre; Pdx1-GFP; LSL-KrasG12D+/-; LSL-Trp53R172H+/- mice were dosed daily by oral gavage, starting at week 6 or week 10, with a concentration of dasatinib (10mg/kg in citrate vehicle; n = 26) which inhibits Src kinase activity but not proliferation, or with vehicle alone (n = 18). Tumor and metastatic burden were assessed by gross pathology and histology. There was a significant reduction in the number of mice with metastases at the time of death (culled due to ill health as per regulatory requirements) when treated with 10 mg/kg dasatinib (30%) compared with vehicle (65%) [p = 0.001], although there was no significant difference in the median overall survival (dasatinib = 129 days; vehicle = 142 days) presumably due to the effects of the primary tumor burden. We conclude that dasatinib, by inhibiting Src kinase activity, inhibits the development of metastases in a mouse model of PDAC which mimics the human disease. It remains to be determined if dasatinib could improve overall survival when used in the adjuvant (post-operative) setting after removal of the primary tumor burden.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-217.