Therapeutic targeting of glutamate dehydrogenase 1 that links metabolic reprogramming and Snail-mediated epithelial-mesenchymal transition in drug-resistant lung cancer

Acquired drug resistance and epithelial-mesenchymal transition (EMT) mediated metastasis are two highly interacting determinants for non-small-cell lung cancer (NSCLC) prognosis. This study investigated the common mechanisms of drug resistance and EMT from the perspective of metabolic reprogramming, which may offer new ideas to improve anticancer therapy. Acquired resistant cells were found to grow faster and have a greater migratory and invasive capacity than their parent cells. Metabolomics analysis revealed that acquired resistant cells highly relied on glutamine utilization and mainly fluxed into oxidative phosphorylation energy production. Further mechanistic studies screened out glutamate dehydrogenase 1 (GLUD1) as the determinant of glutamine addiction in acquired resistant NSCLC cells, and provided evidence that GLUD1-mediated alpha-KG production and the accompanying reactive oxygen species (ROS) accumulation primarily triggered migration and invasion by inducing Snail. Pharmacological and genetic interference with GLUD1 in vitro significantly reversed drug resistance and decreased cell migration and invasion capability. Lastly, the successful application of R162, a selective GLUD1 inhibitor, to overcome both acquired resistance and EMT-induced metastasis in vivo, identified GLUD1 as a promising and druggable therapeutic target for malignant progression of NSCLC. Collectively, our study offers a potential strategy for NSCLC therapy, especially for drug-resistant patients with highly expressed GLUD1.

Automated summary

This study investigates the common mechanisms of drug resistance and epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) from the perspective of metabolic reprogramming. It identifies GLUD1 as a key determinant of glutamine addiction in acquired resistant NSCLC cells, and shows that GLUD1-mediated alpha-KG production and ROS accumulation primarily trigger migration and invasion. Pharmacological and genetic interference with GLUD1 reverses drug resistance and decreases cell migration and invasion capability. The successful application of a GLUD1 inhibitor overcomes both acquired resistance and EMT-induced metastasis in vivo, demonstrating GLUD1 as a promising therapeutic target for NSCLC progression.