APEX1 and neoplasm: Another synthetic lethal pair involving Ref-1/APE1 and hypoxia is the combination of Ref-1/APE1 inhibition with inhibition of the HIF-1α target CA9.14 Using pancreatic 3D co-culture models, tumor spheroid area is reduced after dual targeting with Ref-1/APE1 and CA9 (Fig. 2).