Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy
Journal
Nature cancer
Journal Volume
5
Journal Issue
3
Date Issued
2024-03
Author(s)
Huang, Yu-Kai
Cheng, Wei-Chung
Kuo, Ting-Ting
Yang, Juan-Cheng
Wu, Yang-Chang
Wu, Heng-Hsiung
Lo, Chia-Chien
Hsieh, Chih-Ying
Wong, Sze-Ching
Lu, Chih-Hao
Wu, Wan-Ling
Liu, Shih-Jen
Li, Yi-Chuan
Lin, Ching-Chan
Shen, Chia-Ning
Hung, Mien-Chie
Yeh, Chun-Chieh
Sher, Yuh-Pyng
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 (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.
Publisher
Nature Research
Type
journal article