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Engineering aptamer-directed phosphatase recruiting chimeras: a strategy for modulating receptor function and
Zhilan Zhou1,2, Yichang Liu3, Ya Wang2
1Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China.
Abstract:
Receptor tyrosine kinases (RTKs) play a crucial role in the regulation of intracellular signal transduction, underscoring their significance as targets for drug therapy. Despite the widespread clinical use of kinase inhibitors, the increasing occurrence of off-target effects and drug resistance makes it urgent to explore alternative approaches to modulate RTKs functions. Here, we propose an approach for attenuating cell-surface receptor signaling, termed Aptamer-directed Phosphatase Recruiting Chimeras (Apt-PRCs). The Apt-PRC is composed of an aptamer to recruit phosphatases and a binder to target receptors. As a proof-of-concept, we design and construct Apt-PRCs intended for direct dephosphorylation of tyrosine residues on the receptor targets, i.e., epidermal growth factor receptor and mesenchymal-epithelial transition factor, respectively. The as-developed Apt-PRCs manage to inhibit specifically and efficiently the reception and transmission of phosphorylation signals both in vitro and in vivo. Furthermore, it is discovered that the induced dephosphorylation could enhance the susceptibility to gefitinib in drug-resistant cancer cells and a xenograft mouse model, indicating the potential of Apt-PRCs to overcome drug resistance in cancer. This work offers a versatile methodology to design molecular mediators to modulate receptor phosphorylation so as to regulate the downstream signal transduction and overcome drug resistance.
Insights
We developed Aptamer-directed Phosphatase Recruiting Chimeras (Apt-PRCs) to dephosphorylate cell-surface receptors, offering a new strategy to overcome cancer drug resistance by targeting receptor tyrosine kinases.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Receptor tyrosine kinases (RTKs) are crucial in cell signaling and cancer development.
- Current kinase inhibitors face challenges with off-target effects and drug resistance.
- Novel strategies are needed to modulate RTK function effectively.
Purpose of the Study:
- To develop a novel approach, Aptamer-directed Phosphatase Recruiting Chimeras (Apt-PRCs), for attenuating cell-surface receptor signaling.
- To demonstrate the efficacy of Apt-PRCs in dephosphorylating specific RTKs like EGFR and MET.
- To evaluate the potential of Apt-PRCs in overcoming drug resistance in cancer.
Main Methods:
- Design and construction of Apt-PRCs, comprising an aptamer for phosphatase recruitment and a binder for receptor targeting.
- In vitro and in vivo experiments to assess the dephosphorylation activity and signaling inhibition by Apt-PRCs.
- Evaluation of Apt-PRC efficacy in enhancing sensitivity to gefitinib in drug-resistant cancer models.
Main Results:
- Apt-PRCs successfully achieved direct dephosphorylation of target RTKs (EGFR, MET).
- Apt-PRCs demonstrated specific and efficient inhibition of phosphorylation signal reception and transmission.
- Induced dephosphorylation by Apt-PRCs enhanced gefitinib sensitivity in resistant cancer cells and a mouse model.
Conclusions:
- Apt-PRCs represent a versatile methodology for modulating receptor phosphorylation and downstream signaling.
- This approach shows significant potential for overcoming drug resistance in cancer therapy.
- Apt-PRCs offer a promising alternative strategy for targeting RTK signaling pathways.
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