Targeting ADAM9: A New Pathway to Combat Pancreatic Cancer

This study identifies ADAM9, a disintegrin and metalloproteinase, as a critical stabilizer of wild-type and mutant KRAS proteins in pancreatic ductal adenocarcinoma (PDAC). Loss of ADAM9 enhances the interaction between KRAS and plasminogen activator inhibitor 1 (PAI-1), which acts as an autophagy receptor, triggering selective lysosomal degradation of KRAS. Using a small-molecule ADAM9 inhibitor, researchers demonstrated reduced tumor progression in spontaneous PDAC models. Moreover, combining ADAM9 inhibition with gemcitabine, a chemotherapy standard, resulted in significant tumor regression in patient-derived models. This approach offers a novel therapeutic avenue to disrupt KRAS signaling and improve chemotherapy sensitivity in PDAC, addressing a critical unmet clinical need.