EGFR/HER-1 Inhibitor Exert Cardiotoxicity Through Energy Metabolic Reprogramming

Objective To investigate the toxicity effect and mechanism of epidermal growth factor receptor(EGFR)/HER-1 inhibitors on cardiomyocytes.

Methods Cardiomyocytes were treated with EGFR / HER-1 inhibitor (AG1478) at different concentrations (100 nmol/L, 1 μmol/L, 10 μmol/L) for 48 hours, and then the concentrations of glucose and lactate in the supernatant were detected. The oxygen-glucose deprivation cell model of cardiomyocytes was established, and the effects of AG1478 on apoptosis, ATP production and mitochondrial membrane potential were tested. After AG1478 treatment in cardiomyocytes, transcriptome sequencing was performed, and KEGG (Kyoto Encyclopedia of Genes and Genomes), differentially expressed genes and protein interaction networks were analyzed.

Results AG1478 decreased glucose utilization and increased lactate production in cardiomyocytes in a concentration-dependent manner and promoted oxygen-glucose deficiency induced myocardial cell death. AG1478 promoted mitochondrial damage, reduced ATP production and induced apoptosis of cardiomyocytes. AG1478 affected energy metabolic pathways such as pyruvate metabolism, cysteine and methionine metabolism, and glycolytic metabolism in cardiomyocytes, resulting in significant differences in the expression of mitochondrial enzymes and lactate dehydrogenases such as PCK2 and LDHB, and it was found that LDHAL6B, which activates lactate dehydrogenase, interacted with mitochondrial enzyme PCK2.

Conclusions AG1478 promotes cardiomyocyte apoptosis through glucose metabolic reprogramming, mitochondrial damage, and energy metabolism imbalance, resulting in cardiomyocyte toxicity. The results of this study provides important evidences for clinical to prevent cardiotoxicity from using EGFR/HER-1 targeted drugs in non-small cell lung cancer.