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 () and Liang Li ()
Additional contact information
Hongjuan Yao: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Wenping Song: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Rui Cao: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Cheng Ye: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Li Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Hebing Chen: Beijing Institute of Radiation Medicine
Junting Wang: Beijing Institute of Radiation Medicine
Yuchen Shi: Beijing University of Chinese Medicine
Rui Li: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Yi Li: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Xiujun Liu: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Xiaofei Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Rongguang Shao: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)
Liang Li: Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)

Nature Communications, 2022, vol. 13, issue 1, 1-24

Abstract: 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 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-33037-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33037-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-33037-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().