國家衛生研究院 NHRI:Item 3990099045/15657

NHRI > National Institute of Infectious Diseases and Vaccinology > Shih-Jen Liu > Periodical Articles > Item 3990099045/15657

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/15657

Title:	Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy
Authors:	Huang, YK;Cheng, WC;Kuo, TT;Yang, JC;Wu, YC;Wu, HH;Lo, CC;Hsieh, CY;Wong, SC;Lu, CH;Wu, WL;Liu, SJ;Li, YC;Lin, CC;Shen, CN;Hung, MC;Lin, JT;Yeh, CC;Sher, YP
Contributors:	National Institute of Infectious Diseases and Vaccinology
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. Huang et al. show that ADAM9 loss upregulates PAI-1, promoting its interaction with KRAS and resulting in selective lysosomal degradation of KRAS. They also identify a small-molecule inhibitor of ADAM9 with therapeutic benefits in the context of PDAC.
Date:	2024-03
Relation:	Nature Cancer. 2024 Mar;5(3):400-419.
Link to:	http://dx.doi.org/10.1038/s43018-023-00720-x
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2662-1347&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:001149827500002
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85183028374
Appears in Collections:	[Shih-Jen Liu] Periodical Articles

Files in This Item:

File	Description	Size	Format
ISI001149827500002.pdf		29326Kb	Adobe PDF	75	View/Open

Loading...