ADAM9 deficiency mediates KRAS related pathways in pancreatic cancer cells

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE245560 | GEO | 2023/12/11

REPOSITORIES: GEO