Halofuginone targets Serine/Glycine synthesis to reverse epidermal growth factor receptor Tyrosine Kinase inhibitor resistance in lung adenocarcinoma

作者：Yongping Li, Peipei Liu, Shiyao Liu, Juan Zhu, Yuehua Han, Zuojie Jiang, Dawei Tang, Zixuan Meng, Shanshan Li, Mengxiao Zhang, Yunlei Fan, Fangtian Fan, Pei Zhang, Hao Liu · 发表于：Phytomedicine · 年份：2025 · DOI：10.1016/j.phymed.2025.156788 · 被引用次数：2 · 研究领域：Quinazolinone synthesis and applications、Alkaloids: synthesis and pharmacology、Bioactive natural compounds

• Reduced sensitivity of NSCLC cells to EGFR-TKI after resistance. • Halofuginone overcomes NSCLC resistance to EGFR-TKIs. • Halofuginone inhibits the synthesis of serine and glycine in tumor cells. • Validation of the Specificity protein 1 binding site on the phosphatidylserine transcarbamoylase 1 promoter. An emerging issue is that patients are prone to become resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) which are the first- line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) after approximately 10 months of drug administration. Interestingly, metabolic dysregulation occurs simultaneously with acquired EGFR-TKI resistance in certain NSCLC cell lines. We aimed to investigate whether a natural product, halofuginone (HF), could overcome NSCLC resistance to EGFR-TKIs by influencing metabolism. In our study, the combination of HF and EGFR-TKI exhibited synergistic cytotoxicity compared to EGFR-TKI monotherapy. The underlying mechanism is that HF promotes the degradation of SP1 protein and decreases the expression of phosphatidylserine transcarbamoylase 1 (PSAT1), which leads to defects in the de novo synthesis of Serine/Glycine and cell death. HF is a promising natural product for overcoming NSCLC resistance to third-generation epidermal growth factor receptors-TKIs.