An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms.
Hongjuan YaoWenping SongRui CaoCheng YeLi ZhangHebing ChenJunting WangYuchen ShiRui LiYi LiXiujun LiuXiaofei ZhouRongguang ShaoLiang LiPublished in: Nature communications (2022)
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.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- signaling pathway
- locally advanced
- cancer therapy
- small cell lung cancer
- induced apoptosis
- epidermal growth factor receptor
- pi k akt
- primary care
- squamous cell carcinoma
- drug delivery
- cell proliferation
- transcription factor
- tyrosine kinase
- radiation therapy
- mouse model
- mesenchymal stem cells
- smoking cessation