Details

Autor(en) / Beteiligte

• 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
• Lin, Jaw-Town
• Yeh, Chun-Chieh
• Sher, Yuh-Pyng

Titel

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

Ist Teil von

• Nature cancer, 2024-03, Vol.5 (3), p.400

Ort / Verlag

England

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.