Pathological Mechanistic Studies of Osimertinib Resistance in Non-Small-Cell Lung Cancer Cells Using an Integrative Metabolomics-Proteomics Analysis

BACKGROUND: Osimertinib is the first-line therapeutic option for the T790M-mutant non-small-cell lung cancer and the acquired resistance obstructs its application. It is an urgent challenge to identify the potential mechanisms of osimertinib resistance for uncovering some novel therapeutic approaches. METHODS: In the current study, the cell metabolomics based on ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry and the qualitative and tandem mass tags quantitative proteomics were performed. RESULTS: 54 differential metabolites and 195 differentially expressed proteins were, respectively, identified. The amino acids metabolisms were significantly altered. HIF-1 signaling pathway modulating P-glycoproteins expression, PI3K-Akt pathway regulating survivin expression, and oxidative phosphorylation were upregulated, while arginine and proline metabolism regulating NO production and glycolysis/gluconeogenesis were downregulated during osimertinib resistance. CONCLUSION: The regulation of HIF-1 and PI3K-Akt signaling pathway, energy supply process, and amino acids metabolism are the promising therapeutic tactics for osimertinib resistance.