Wang Ya, Zhang Guixi, Zhou Zhilan, Zhang Ning, Jiang Hang, Liu Yichang, Fu Ting, Zhu Yingdi, Li Juan
School of Chemistry and Materials, University of Science and Technology of China, Hefei, 230026, China.
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China.
Adv Healthc Mater. 2025 Jan;14(2):e2402884. doi: 10.1002/adhm.202402884. Epub 2024 Nov 25.
Non-small cell lung cancers (NSCLC) frequently acquire resistance to tyrosine kinase inhibitors (TKI) due to epidermal growth factor receptor (EGFR) mutation or activation of the bypass pathway involving mesenchymal-epithelial transition factor (Met). To address this challenge, a bispecific nanobody-aptamer chimera is designed to target mutated EGFR and Met simultaneously to block their cross-talk in NSCLC. The EGFR-Met chimera is cost-effectively engineered using microbial transglutaminase and click chemistry strategies. With enhanced binding affinity toward the target proteins, the as-developed chimera inhibits efficiently the cross-talk between signaling pathways associated with EGFR and Met. This inhibition leads to the suppression of downstream pathways, such as Erk and Akt, and induces upregulation of cell cycle arrest-related proteins, including Rb, p21, and p27. Additionally, the chimera activates the caspase-dependent apoptotic signaling pathway. Consequently, it inhibits cell migration, induces cell death, and causes cell cycle arrest in vitro. Moreover, the chimera exhibits significant antitumor efficacy in drug-resistant xenograft mouse models, showcasing improved tissue penetration and low toxicity. This study accentuates the potential of the bispecific EGFR-Met chimera as a promising therapeutic option for NSCLC resistant to EGFR TKIs.
非小细胞肺癌（NSCLC）常因表皮生长因子受体（EGFR）突变或涉及间充质-上皮转化因子（Met）的旁路途径激活而对酪氨酸激酶抑制剂（TKI）产生耐药性。为应对这一挑战，设计了一种双特异性纳米抗体-适配体嵌合体，以同时靶向突变的EGFR和Met，阻断它们在NSCLC中的相互作用。利用微生物转谷氨酰胺酶和点击化学策略，以经济高效的方式构建了EGFR-Met嵌合体。所开发的嵌合体对靶蛋白具有增强的结合亲和力，有效抑制了与EGFR和Met相关的信号通路之间的相互作用。这种抑制导致下游通路（如Erk和Akt）的抑制，并诱导细胞周期停滞相关蛋白（包括Rb、p21和p27）的上调。此外，嵌合体激活了半胱天冬酶依赖性凋亡信号通路。因此，它在体外抑制细胞迁移、诱导细胞死亡并导致细胞周期停滞。此外，该嵌合体在耐药异种移植小鼠模型中表现出显著的抗肿瘤疗效，显示出改善的组织穿透性和低毒性。本研究强调了双特异性EGFR-Met嵌合体作为EGFR TKI耐药NSCLC的一种有前景的治疗选择的潜力。
