Cytosolic malic enzyme and glucose-6-phosphate dehydrogenase modulate redox balance in NSCLC with acquired drug resistance.

Lung cancer cells often show elevated levels of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH). However, the connections between deregulated redox homeostasis in different subtypes of lung cancer and acquired drug resistance in lung cancer have not yet been fully established. Herein, we analyzed different subtypes of lung cancer data reported in the Cancer Cell Line Encyclopedia database, the Cancer Genome Atlas program, and the sequencing data obtained from a gefitinib-resistant non-small cell lung cancer (NSCLC) cell line (H1975GR). Using flux balance analysis model integrated with multi-omics data and gene expression profiles, we identified cytosolic malic enzyme 1 and glucose-6-phosphate dehydrogenase as the major contributors to the significantly upregulated NADPH flux in NSCLC tissues as compared with normal lung tissues, and gefitinib-resistant NSCLC cell line as compared with the parental cell line. Silencing the gene expression of either of these two enzymes in two osimertinib-resistant NSCLC cell lines (H1975OR and HCC827OR) exhibited strong anti-proliferative effects. Our findings not only underscored the pivotal roles of cytosolic malic enzyme 1 and glucose-6-phosphate dehydrogenase in regulating redox states in NSCLC cells but also provided novel insights into their potential roles in drug-resistant NSCLC cells with disturbed redox states.