An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC

Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small-molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies is often ineffective in treating cancers harboring wild-type EGFR. Given the fact that EGFR possesses a kinase-independent pro-survival f...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-09, Vol.24 (18), p.14012
Main Authors: Huang, Yanping, Cuan, Xiangdan, Zhu, Weiwei, Yang, Xingying, Zhao, Yunli, Sheng, Jun, Zi, Chengting, Wang, Xuanjun
Format: Article
Language:English
Subjects:
Cancer
Cancer therapies
Care and treatment
Catechin
Drug dosages
Epidermal growth factor
FDA approval
Hydrogen bonds
Kinases
Lung cancer
Lung cancer, Non-small cell
Medical prognosis
Natural products
Nimotuzumab
NSCLC
Signal transduction
theasinensin A
Toxicity
Tyrosine
wild-type EGFR
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Summary:Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small-molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies is often ineffective in treating cancers harboring wild-type EGFR. Given the fact that EGFR possesses a kinase-independent pro-survival function, more effective inhibition of EGFR-mediated signals is therefore necessary. In this study, we investigated the effects of using a combination of low-dose nimotuzumab and theasinensin A to evaluate whether the inhibitory effect of nimotuzumab on NCI-H441 cancer cells was enhanced. Here, theasinensin A, a novel epigallocatechin-3-gallate (EGCG) derivative, was identified and its potent anticancer activity against wild-type EGFR NSCLC was demonstrated in vitro; the anticancer activity was induced through degradation of EGFR. Mechanistic studies further revealed that theasinensin A bound directly to the EGFR extracellular domain, which decreased interaction with its ligand EGF in combination with nimotuzumab. Theasinensin A significantly promoted EGFR degradation and repressed downstream survival pathways in combination with nimotuzumab. Meanwhile, treatment with theasinensin A and nimotuzumab prevented xenograft growth, whereas the single agents had limited effect. Thus, the combination therapy of theasinensin A with nimotuzumab is a powerful candidate for treatment of wild-type EGFR cancers.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241814012