Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells

Simple Summary Non-small cell lung cancer (NSCLC) patients harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) inevitably develop resistance to targeted EGFR tyrosine kinase inhibitors (TKI) therapy. To support malignant features associated with cancer development and therapy resistance, the cancer cells adapt their metabolic rate and pathways. As an example, aerobic glycolysis, where the cells use glycolysis in the presence of oxygen, is frequently seen. Here we show that targeting aerobic glycolysis represents a promising strategy in cancer therapeutics. Increased glycolytic activity is a hallmark of cancer initiation and progression and is often observed in non-small cell lung cancer (NSCLC). Pyruvate dehydrogenase (PDH) complex acts as a gatekeeper between glycolysis and oxidative phosphorylation, and activation of PDH is known to inhibit glycolytic activity. As part of a standard therapeutic regimen, patients with NSCLC harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) are treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). Independent of good initial response, development of resistance to this therapy is inevitable. In the presented work, we propose that inhibition of glycolysis will add to the therapeutic effects and possibly prevent development of resistance against both EGFR TKIs and ionizing radiation in NSCLC. Analysis of transcriptome data from two independent NSCLC patient cohorts identified increased expression of pyruvate dehydrogenase kinase 1 (PDHK1) as well as upregulated expression of genes involved in glucose metabolism in tumors compared to normal tissue. We established in vitro models of development of resistance to EGFR TKIs to study metabolism and determine if targeting PDHK would prevent development of resistance to EGFR TKIs in NSCLC cells. The PDHK1 inhibitor dichloroacetate (DCA) in combination with EGFR TKIs and/or ionizing radiation was shown to increase the therapeutic effect in our NSCLC cell models. This mechanism was associated with redirected metabolism towards pyruvate oxidation and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Using DCA, the intracellular pool of pyruvate available for lactic fermentation becomes limited. Consequently, pyruvate is redirected to the mitochondria, and reinforces mitochondrial activity. Addition of DCA to cell culture deacidifies the extracellular microenvironment as less lactate is produced and excreted. In our study, we find that this redirection of metabolism adds to the therapeutic effect of EGFR TKI and ionizing radiation in NSCLC.

Automated summary

In patients with non-small cell lung cancer (NSCLC), targeting aerobic glycolysis can enhance the therapeutic effects of EGFR tyrosine kinase inhibitors (EGFR TKIs) and ionizing radiation, potentially preventing the development of resistance. This study suggests that inhibiting glycolysis could redirect metabolism towards pyruvate oxidation and reduce lactate production, leading to increased mitochondrial activity and deacidification of the extracellular microenvironment, ultimately enhancing the efficacy of EGFR TKIs and ionizing radiation in NSCLC.