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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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/18/14012 |
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| author | Yanping Huang Xiangdan Cuan Weiwei Zhu Xingying Yang Yunli Zhao Jun Sheng Chengting Zi Xuanjun Wang |
| author_facet | Yanping Huang Xiangdan Cuan Weiwei Zhu Xingying Yang Yunli Zhao Jun Sheng Chengting Zi Xuanjun Wang |
| author_sort | Yanping Huang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T22:40:01Z |
| format | Article |
| id | doaj.art-22738698dd6d483a820f232dee1915b5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:40:01Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-22738698dd6d483a820f232dee1915b52023-11-19T11:06:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181401210.3390/ijms241814012An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLCYanping Huang0Xiangdan Cuan1Weiwei Zhu2Xingying Yang3Yunli Zhao4Jun Sheng5Chengting Zi6Xuanjun Wang7Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming 650201, ChinaInhibiting 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.https://www.mdpi.com/1422-0067/24/18/14012nimotuzumabtheasinensin Awild-type EGFRNSCLC |
| spellingShingle | Yanping Huang Xiangdan Cuan Weiwei Zhu Xingying Yang Yunli Zhao Jun Sheng Chengting Zi Xuanjun Wang An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC International Journal of Molecular Sciences nimotuzumab theasinensin A wild-type EGFR NSCLC |
| title | An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC |
| title_full | An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC |
| title_fullStr | An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC |
| title_full_unstemmed | An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC |
| title_short | An EGCG Derivative in Combination with Nimotuzumab for the Treatment of Wild-Type EGFR NSCLC |
| title_sort | egcg derivative in combination with nimotuzumab for the treatment of wild type egfr nsclc |
| topic | nimotuzumab theasinensin A wild-type EGFR NSCLC |
| url | https://www.mdpi.com/1422-0067/24/18/14012 |
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