Research On Effect And Mechanism Of Phosphoserine Aminotransferase 1 In EGFR-TKIs Resistance In Lung Adenocarcinoma

Molecular-targeted drugs represented by epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)have been widely developed and applied to the treatment of lung adenocarcinoma,but the recurrence and emergence of drug resistance has become a major obstacle to clinical treatment.Therefore,it is crucial important to find new targets and combination treatment strategies to overcome the drug resistance,it has also been a research hotspot.Known mechanisms of drug resistance include the mutations of target gene,the activation of bypass pathways or downstream pathway,among which metabolic reprogramming regulatory mechanisms are receiving increasing attention.Phosphoserine aminotransferase 1(PSAT1),a key enzyme in the serine biosynthesis pathway,catalyzes the serine and glycine biosynthesis and participates in one-carbon unit cycle,meanwhile catalyzing the production of α-ketoglutaric acid by glutamate,and then flux in the Krebs cycle,which plays a key role in the metabolic regulation network and is closely related to the development of various cancers.Clinical data shows that the abnormal overexpression of PSAT1 is negatively correlated with the prognosis of patients with lung adenocarcinoma.This research focused on the effect and mechanism of PSAT1 in lung adenocarcinoma EGFR-TKIs drug resistance.First,it was found that the expression levels of the serine biosynthesis pathway enzymes including PSAT1 was all increased in lung adenocarcinoma cells after the short-time treatment with EGFR-TKIs,and the synthesis of serine and downstream pathway products were also up-regulated subsequently;Then,the EGFR-TKIs acquired resistant lung adenocarcinoma cell line(hereinafter referred to as resistant cells)was established by dosage escalation of EGFR-TKIs.The results of in vitro and in vivo experiments both showed that compared with the sensitive cells,the protein and m RNA levels of PSAT1 in resistant cells were significantly increased.2.Down-regulation of PSAT1 selectively inhibited the proliferation of resistant cells and it could overcome drug resistance.3.Down-regulation of PSAT1 can also inhibited the subcutaneous xenografts growth and the occurrence of drug resistance.Afterwards,we constructed a cell line that overexpresses PSAT1 in vitro.Reverse validation experiments showed that 1.PSAT1 could enhance the proliferation of lung adenocarcinoma cells;2.PSAT1 can promote the growth of subcutaneous xenografts of lung adenocarcinoma cells.and inducementof drug resistance in vivo;Further mechanism research showed that down-regulation of PSAT1 selectively caused active oxygen accumulation in drug-resistant cells to activate the JNK/c-Jun signaling pathway,leading to DNA damage and apoptosis in cells,thereby overcoming drug resistance.This study found that PSAT1 can mediate the adaptive and acquired drug resistance process of lung adenocarcinoma for the frist time,and inhibition of PSAT1 can effectively overcome the resistance to of lung cancer adenocarcinoma both one and three-generation EGFR-TKIs,suggesting that PSAT1 is expected to become a promising therapeutic target of drug resistance.It has important clinical significance for guiding individualized treatment of lung adenocarcinoma.