Through the integration of ATF4 activity assays, phospho-specific antibodies to indicate activity, 3D co-culture assays, and the use of selective small molecule inhibitors of Ref-1, PERK, and GCN2, we have discovered that the co-culture of pancreatic cancer cells and CAFs respond to the blockade of Ref-1 redox signaling through phosphorylation of PERK and eIF2α. Here, EIF2A is linked to familial pancreatic carcinoma.