Interference with PADI1 and PADI3 re-sensitizes KRAS-Mutant PDAC and CRC to KRAS ON/OFF Inhibitors by Promoting Non-lytic Apoptosis

However, intrinsic or acquired resistance significantly limited their clinical potential. In this study, we demonstrated that in CRC, LUAD, and PDAC patients harboring activating KRAS mutations the expression of peptidylarginine deiminases PADI1 and, most notably, PADI3 represented negative prognostic markers.

KRAS-driven metabolic rewiring, hypoxia, and acidosis sustained PADI1 and PADI3 expression through activation of an upstream enhancer of PADI1. KRAS inhibition resulted in loss of PADI1 and PADI3 expression, whereas cellular models resistant to enforced KRAS degradation maintained basal expression levels of PADI1 and 3. Pharmacological inhibition of PADIs using BBCl amidine or two selective PADI3 inhibitors synergized with KRAS-ON and KRAS-OFF inhibitors in two- and three-dimensional CRC and PDAC models, as well as in a PDAC murine xenograft.