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

Background: 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.

Purpose: We aimed to investigate whether a natural product, halofuginone (HF), could overcome NSCLC resistance to EGFR-TKIs by influencing metabolism.

Results: 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.

Conclusions: HF is a promising natural product for overcoming NSCLC resistance to third-generation epidermal growth factor receptors-TKIs.

EGFR-TKI; Halofuginone; NSCLC; Resistance; Serine/Glycine.