Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy
Menée à l'aide de lignées cellulaires, de cultures tridimensionnelles, de modèles murins, de données du projet "The Cancer Genome Atlas" et d'échantillons tumoraux issus de patients atteints d'un adénocarcinome canalaire du pancréas, cette étude démontre que l'inhibition de l'enzyme ADAM9 favorise la dégradation sélective de KRAS et sensibilise les cellules cancéreuses à la chimiothérapie
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 (ADAM)9 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 light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and 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.
Nature Cancer , résumé, 2024