Zhou Zhilan, Liu Yichang, Wang Ya, Jiang Hang, Chen Tingting, Zhu Yingdi, Fu Ting, Li Juan
Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China.
Nat Commun. 2025 Apr 25;16(1):3919. doi: 10.1038/s41467-025-59098-2.
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.
受体酪氨酸激酶（RTKs）在细胞内信号转导调节中起关键作用，凸显了它们作为药物治疗靶点的重要性。尽管激酶抑制剂在临床上广泛应用，但脱靶效应和耐药性的日益增加使得探索调节RTKs功能的替代方法变得紧迫。在此，我们提出一种减弱细胞表面受体信号传导的方法，称为适体导向磷酸酶招募嵌合体（Apt-PRCs）。Apt-PRC由用于招募磷酸酶的适体和靶向受体的结合剂组成。作为概念验证，我们设计并构建了分别用于直接使受体靶点（即表皮生长因子受体和间充质-上皮转化因子）上的酪氨酸残基去磷酸化的Apt-PRCs。所开发的Apt-PRCs在体外和体内均能特异性且有效地抑制磷酸化信号的接收和传递。此外，研究发现诱导的去磷酸化可增强耐药癌细胞和异种移植小鼠模型对吉非替尼的敏感性，表明Apt-PRCs具有克服癌症耐药性的潜力。这项工作提供了一种通用的方法来设计分子介质，以调节受体磷酸化，从而调节下游信号转导并克服耐药性。
