Huang, Yu-KaiYu-KaiHuangCheng, Wei-ChungWei-ChungChengKuo, Ting-TingTing-TingKuoYang, Juan-ChengJuan-ChengYangWu, Yang-ChangYang-ChangWuWu, Heng-HsiungHeng-HsiungWuLo, Chia-ChienChia-ChienLoHsieh, Chih-YingChih-YingHsiehWong, Sze-ChingSze-ChingWongLu, Chih-HaoChih-HaoLuWu, Wan-LingWan-LingWuLiu, Shih-JenShih-JenLiuLi, Yi-ChuanYi-ChuanLiLin, Ching-ChanChing-ChanLinShen, Chia-NingChia-NingShenHung, Mien-ChieMien-ChieHungJAW-TOWN LINYeh, Chun-ChiehChun-ChiehYehSher, Yuh-PyngYuh-PyngSher2024-03-282024-03-282024-032662-1347https://www.scopus.com/record/display.uri?eid=2-s2.0-85183028374&doi=10.1038%2fs43018-023-00720-x&origin=inward&txGid=e9a0e5dc11c221be653595f408e727dbhttps://scholars.lib.ntu.edu.tw/handle/123456789/641526Kirsten 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.enjournal article10.1038/s43018-023-00720-x382676272-s2.0-85183028374https://api.elsevier.com/content/abstract/scopus_id/85183028374