An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms

• DOI: 10.1038/s41467-022-33037-x
• Publication Date: 2022-09-20T10:13:55Z
• Authors: Hongjuan Yao; Wenping Song; Rui Cao; Cheng Ye; Li Zhang; Hebing Chen; Junting Wang; Yuchen Shi; Rui Li; Yi Li; Xiujun Liu; Xiaofei Zhou; Rongguang Shao; Liang Li
• Keywords: 0301 basic medicine; Science; TOR Serine-Threonine Kinases; Q; NF-kappa B; Ligands; Deoxycytidine; Gemcitabine; Article; 3. Good health; ErbB Receptors; Pancreatic Neoplasms; 03 medical and health sciences; Aminoglycosides; Cell Line, Tumor; Humans; Enediynes; Carcinoma, Pancreatic Ductal; Smad4 Protein

Abstract Chemoresistance limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an EGFR/HER2 targeted conjugate, dual-targeting ligand-based lidamycin (DTLL), which shows a highly potent antitumor effect. To overcome chemoresistance in PDAC, we aim to study DTLL efficacy when combined with gemcitabine and explore mechanisms of action. combination show superior inhibitory effect on the growth gemcitabine-resistant/sensitive tumors. sensitizes via distinct action mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation ATK/mTOR blockade NF-κB impaired function SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity trigger downstream NF-κB-regulated signaling SMAD4-deficient tumors chemoresistance. seems act as module that normalizes having synergistic gemcitabine. Our findings provide insight into rational SMAD4-directed precision therapy PDAC.