3239

MAPK/ERK kinase (MEK1/2) is an integral component of the RAS/RAF/MEK/ERK signaling pathway implicated in uncontrolled cell proliferation and cell survival. AZD6244 (ARRY-142886), a novel, selective, ATP uncompetitive inhibitor of MEK1/2 is currently in phase II clinical trials in a range of diseases including pancreatic cancer. In this study, we have assessed the activity of AZD6244 in vitro across a panel of 11 pancreatic tumor cell lines using cell viability assays. These lines have been characterized for their Ras/Raf mutational status. Despite consistent inhibition of ERK1/2 phosphorylation, a range of sensitivities were observed (31 nM to complete resistance). Pathway activation was assessed by determining the expression of phospho-MEK1/2 and phospho-ERK1/2. The anti-tumor activity of AZD6244 (oral gavage, 3 or 10 mg/kg twice daily) was also tested in vivo using nude mice subcutaneously implanted with the human pancreatic tumor xenografts AsPC-1 and HPAC. Dose-dependent inhibition of tumor growth was observed in both xenograft models with AZD6244-treated groups versus vehicle controls (HPAC 66% and 56% inhibition (P<0.0001), respectively, at 10 and 3 mg/kg twice daily; AsPC-1 60% and 51% inhibition (P<0.0001), respectively, at 10 and 3 mg/kg twice daily). In addition to determining monotherapy activity, we have also assessed the interactions of AZD6244 with Gemcitabine when dosed in combination in all 11 cell lines using both concurrent and sequential schedules. The nature of the interaction between AZD6244 and Gemcitabine is cell line dependant, with both beneficial and antagonistic interactions being observed. The data provided in these studies illustrate the benefits of examining cell line panels to validate both the monotherapy and combination therapy potential of drug candidates.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA