Inhibition of ADAM9 mediates KRAS-related pathways in pancreatic cancer cells
Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here we identify a disintegrin and metalloproteinase domain 9 (ADAM9) as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor-1 (PAI-1), which functions as a selective autophagy receptor in conjunction with LC3, triggering the lysosomal degradation of KRAS. Suppression of ADAM9 by a small molecule inhibitor restricts disease progression in spontaneous models, and the combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC. Overall design: Comparative gene expression profiling analysis of RNA-seq data for ADAM9i-treated PDAC103P cells and its vehicle control (Vehicle and ADAM9i).