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

Qing Ma,Jing Wang,Lili Zeng,Fanlu Meng,Yaoyao Ren

doi:10.1155/2020/6249829

Abstract

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.

Highlights

Lung cancer, especially non-small-cell lung cancer (NSCLC) which accounts for more than 80% of lung cancer cases [1], has become one of the most common and lethal cancers with 16% morbidity and 18.4% mortality among all kinds of malignant cancers [2]
Blocking of mTOR activity reinforced the sensitivity to epidermal growth factor receptor- (EGFR-)TKIs in glioma cells, while mTOR is a downstream signaling molecule of PI3K-PTEN-Akt pathway [20]
In the study, a multiomics tactics by integrating metabolomics and proteomics was performed to identify the potential mechanism of osimertinib resistance of human non-small-cell lung adenocarcinoma cell

Summary

Introduction

Especially non-small-cell lung cancer (NSCLC) which accounts for more than 80% of lung cancer cases [1], has become one of the most common and lethal cancers with 16% morbidity and 18.4% mortality among all kinds of malignant cancers [2]. For the EGFR-mutant NSCLC patients, EGFR-tyrosine kinase inhibitors (EGFR-TKIs), which can effectively bind to the ATP-binding pocket of the EGFR-tyrosine kinase domain to block downstream signaling pathway, have become the preferred targeted therapy [4,5,6]. Osimertinib, as an irreversible EGFR-TKI, does influence the treatment strategy for T790M-mutant NSCLC patients with approximately 60% objective response rate and 9 months’ duration of progression-free survival [9,10,11]. Osimertinib is the first-line therapeutic option for the T790M-mutant non-small-cell lung cancer and the acquired resistance obstructs its application. E regulation of HIF-1 and PI3K-Akt signaling pathway, energy supply process, and amino acids metabolism are the promising therapeutic tactics for osimertinib resistance Conclusion. e regulation of HIF-1 and PI3K-Akt signaling pathway, energy supply process, and amino acids metabolism are the promising therapeutic tactics for osimertinib resistance

Methods

Results

Discussion

Conclusion