KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA), but remains an intractable pharmacological target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here we demonstrate that expression of BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H result in lethal PDA. We tested pharmacologic inhibitors of Ras effectors against multiple human PDA cell lines. MEK inhibition was highly effective both in vivo and in vitro, and was synergistic with AKT inhibition in most cell lines tested. We demonstrate that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA.

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