Metabolomics Of Active Aldehyde In Lung Cancer Cells With EGFR-TKI Acquired Drug Resistance

Lung cancer is the leading cause of cancer-related death in the world today.EGFR Tyrosine kinase inhibitors(EGFR-TKI)has been proposed for the treatment of lung adenocarcinoma targeting EGFR mutations.Unfortunately,drug resistance is inevitable in lung cancer patients,leading to tumor recurrence and poor prognosis after using the targeted drug for a period of time.Metabolic reprogramming plays a vital role in tumor resistance.As a kind of metabolite which can cause oxidative damage to cells,reactive aldehyde promotes and interacts with active oxygen to form "reactive aldehyde-reactive oxygen" axis.Many studies have suggested that tumor resistance is associated with aldehyde dehydrogenase(ALDH)and reactive oxygen species,but there are few studies on reactive aldehydes in drug-resistant cells.Due to the limitations of existing detection methods and insufficient sensitivity,change in the level of reactive aldehydes in lung cancer resistant cells is unclear.Metabonomics,as a new histology,has become a new direction to study the mechanism of drug resistance in tumors.Based on the ultra performance liquid chromatography tandem triple-quadrupole mass spectrometry(UPLC-QQQ/MS)technology platform,we have established an analytical method for detecting the level of reactive aldehydes in cells by derivatization,which improves the detection sensitivity and expands the number of active aldehydes detected.This study suggests a decrease in the level of reactive aldehydes in drug-resistant cells.To investigate the relationship between altered metabolic pathways and reactive aldehydes in drug-resistant cells,we analyzed the metabolic profiling in drug-resistant cells by non-targeted metabolomics based on Ultraperformance liquid chromatography tandem quadrupole time-of-flight mass spectrometry(UPLC-QTOF/MS).We found that glutathione metabolism is most prominently altered in resistant cells.Therefore,we have developed a fast-processing,high-throughput analytical method for target metabolites in GSH metabolic pathway.It is revealed that drug-resistant cells can enhance the GSH metabolic pathway and tolerate a lower intracellular reduction state.This study developed a new targeted analytical method for reactive aldehydes and GSH metabolic pathways,as well as nontargeted analytical method for drug-resistant cell models,which can be applied to other cell models to support research.It also provides a new metabolomics study explanation for lung cancer resistance mechanisms.