https://scholars.lib.ntu.edu.tw/handle/123456789/641526
標題: | Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy | 作者: | 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 JAW-TOWN LIN Yeh, Chun-Chieh Sher, Yuh-Pyng |
公開日期: | 三月-2024 | 出版社: | Nature Research | 卷: | 5 | 期: | 3 | 來源出版物: | Nature cancer | 摘要: | 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. |
URI: | https://www.scopus.com/record/display.uri?eid=2-s2.0-85183028374&doi=10.1038%2fs43018-023-00720-x&origin=inward&txGid=e9a0e5dc11c221be653595f408e727db https://scholars.lib.ntu.edu.tw/handle/123456789/641526 |
ISSN: | 2662-1347 | DOI: | 10.1038/s43018-023-00720-x |
顯示於: | 醫學系 |
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