The Ki-RAS oncogene is altered in pancreatic ductal neoplasms. Pancreatic ductal cells (PDCs) were purified from cytokeratin 19 (K19)-Ki-RAS^G12V transgenic mice and control littermates to identify properties of Ki-Ras activation in a cell-type-specific context. Because Ki-RAS mutation has prognostic significance in patients treated with radiation, we studied the influence of Ki-RAS status on radiation survival.

Pancreatic ductal fragments from mice with Ki-RAS^G12V mutation or wild-type (WT)-Ki-RAS were cultured. Growth curves, electron microscopy, flow cytometry, and analysis of signaling and cell-cycle proteins were established. Farnesyltransferase inhibitor (FTI) treatment with R115777 before and after irradiation was used to determine the effect of Ki-Ras farnesylation on cell survival.

PDCs from WT and K19-Ki-RAS^G12V mice had features of ductal cells with formation of 3-dimensional structures on collagen without differences in morphology, growth, and cell-cycle distribution. This may result from up-regulation of p16INK4 and p27^Kip1 and lack of hyperstimulation of the mitogen-activated protein kinase pathway in Ki-RAS^G12V PDCs. No differences in radiation survival between Ki-RAS^G12V PDCs and WT PDCs were observed. However, Ki-RAS^G12V PDCs expressing mutant p53^V143A had enhanced survival compared with WT PDCs transduced with p53^V143A. R115777 treatment sensitized Ki-RAS^G12V PDCs and Ki-RAS^G12V/p53^V143A PDCs, but not WT PDCs.

Novel characterization of murine WT PDCs and Ki-RAS^G12V PDCs is described. Induction of cell-cycle regulators and lack of mitogen-activated protein kinase hyperstimulation likely are responsible for constraining activated Ki-RAS^G12V-mediated proliferation. Because its activation was required for sensitization by an FTI, R115777 may be useful against pancreatic tumors expressing oncogenic Ki-Ras.