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

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

Nature communications 2022 Sep 20

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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 its mechanisms of action. DTLL in combination with gemcitabine show a superior inhibitory effect on the growth of gemcitabine-resistant/sensitive tumors. DTLL sensitizes gemcitabine efficacy via distinct action mechanisms mediated by mothers against decapentaplegic homolog 4 (SMAD4). It not only prevents neoplastic proliferation via ATK/mTOR blockade and NF-κB impaired function in SMAD4-sufficient PDACs, but also restores SMAD4 bioactivity to trigger downstream NF-κB-regulated signaling in SMAD4-deficient tumors and to overcome chemoresistance. DTLL seems to act as a SMAD4 module that normalizes its function in PDAC, having a synergistic effect in combination with gemcitabine. Our findings provide insight into a rational SMAD4-directed precision therapy in PDAC. © 2022. The Author(s).

Citation

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. An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms. Nature communications. 2022 Sep 20;13(1):5506