Highly Specific Cytokine Receptor-Targeting Chimeras for Targeted Membrane Protein Degradation and Sensitization of Osimertinib in EGFR-Mutated Non-Small-Cell Lung Cancer

Highly Specific Cytokine Receptor-Targeting Chimeras for Targeted Membrane Protein Degradation and Sensitization of Osimertinib in EGFR-Mutated Non-Small-Cell Lung Cancer

© 2025 Wiley‐VCH GmbH.

Bibliographische Detailangaben
Veröffentlicht in:Advanced materials (Deerfield Beach, Fla.). - 1998. - 37(2025), 32 vom: 01. Aug., Seite e2504050
1. Verfasser: Wu, Jiawei (VerfasserIn)
Weitere Verfasser: Gao, Qianqian, Xia, Qing, Wang, Yaru, Zheng, Zixuan, He, Axin, Liu, Yu, Yang, Yang, Miao, Yanyan, Han, Da
Format: Online-Aufsatz
Sprache:English
Veröffentlicht: 2025
Zugriff auf das übergeordnete Werk:Advanced materials (Deerfield Beach, Fla.)
Schlagworte:Journal Article CXCR7 EGFR aptamer cancer therapy targeted protein degradation ErbB Receptors EC 2.7.10.1 Acrylamides osimertinib mehr... 3C06JJ0Z2O Aniline Compounds Receptors, CXCR Aptamers, Nucleotide ACKR3 protein, human EGFR protein, human Antineoplastic Agents Indoles Pyrimidines
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100 1 |a Wu, Jiawei  |e verfasserin  |4 aut 
245 1 0 |a Highly Specific Cytokine Receptor-Targeting Chimeras for Targeted Membrane Protein Degradation and Sensitization of Osimertinib in EGFR-Mutated Non-Small-Cell Lung Cancer 
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500 |a Date Completed 25.08.2025 
500 |a Date Revised 25.08.2025 
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520 |a The ability of cytokine receptors to mediate the internalization of targets in lysosomes positions them as specific and effective effectors for protein degradation strategies. However, challenges remain, including the potential unintended activation of cell-proliferation-related cytokine receptors, as well as limitations in programmability and structural flexibility of protein degradators. In this work, a CXCR7-targeting chimera (AP-CRTAC) that functions as a CXCR7 inducer by covalently linking a membrane protein-targeting aptamer with a mutant-CXCL12 mimic peptide is developed. This peptide selectively binds to CXCR7 without activating CXCR4. The AP-CRTAC, which incorporates various aptamer forms from DNA, RNA, or even bispecific aptamers, has shown significant efficacy in degrading one or more proteins or protein mutants on the cell surface. Moreover, the AP-CRTAC constructed with a 2' F-pyrimidine-modified RNA aptamer targeting EGFR effectively degrades various EGFR activating mutations. Notably, AP-CRTAC enhances the sensitivity of the L858R/T790M/C797S triple mutant lung cancer cells, which are resistant to current EGFR-targeted therapies, to the third-generation EGFR inhibitor osimertinib in both in vitro and in vivo settings. This research introduces an engineered CXCR7 inducer with high specificity and programmability for the targeted degradation of cell surface proteins, while minimizing unwanted side effects 
650 4 |a Journal Article 
650 4 |a CXCR7 
650 4 |a EGFR 
650 4 |a aptamer 
650 4 |a cancer therapy 
650 4 |a targeted protein degradation 
650 7 |a ErbB Receptors  |2 NLM 
650 7 |a EC 2.7.10.1  |2 NLM 
650 7 |a Acrylamides  |2 NLM 
650 7 |a osimertinib  |2 NLM 
650 7 |a 3C06JJ0Z2O  |2 NLM 
650 7 |a Aniline Compounds  |2 NLM 
650 7 |a Receptors, CXCR  |2 NLM 
650 7 |a Aptamers, Nucleotide  |2 NLM 
650 7 |a ACKR3 protein, human  |2 NLM 
650 7 |a EGFR protein, human  |2 NLM 
650 7 |a EC 2.7.10.1  |2 NLM 
650 7 |a Antineoplastic Agents  |2 NLM 
650 7 |a Indoles  |2 NLM 
650 7 |a Pyrimidines  |2 NLM 
700 1 |a Gao, Qianqian  |e verfasserin  |4 aut 
700 1 |a Xia, Qing  |e verfasserin  |4 aut 
700 1 |a Wang, Yaru  |e verfasserin  |4 aut 
700 1 |a Zheng, Zixuan  |e verfasserin  |4 aut 
700 1 |a He, Axin  |e verfasserin  |4 aut 
700 1 |a Liu, Yu  |e verfasserin  |4 aut 
700 1 |a Yang, Yang  |e verfasserin  |4 aut 
700 1 |a Miao, Yanyan  |e verfasserin  |4 aut 
700 1 |a Han, Da  |e verfasserin  |4 aut 
773 0 8 |i Enthalten in  |t Advanced materials (Deerfield Beach, Fla.)  |d 1998  |g 37(2025), 32 vom: 01. Aug., Seite e2504050  |w (DE-627)NLM098206397  |x 1521-4095  |7 nnas 
773 1 8 |g volume:37  |g year:2025  |g number:32  |g day:01  |g month:08  |g pages:e2504050 
856 4 0 |u http://dx.doi.org/10.1002/adma.202504050  |3 Volltext 
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