Please use this identifier to cite or link to this item:
Title: 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
Authors: Dyrstad, Sissel E.
Lotsberg, Maria L.
Tan, Tuan Zea 
Pettersen, Ina K. N.
Hjellbrekke, Silje
Tusubira, Deusdedit
Engelsen, Agnete S. T.
Daubon, Thomas
Mourier, Arnaud
Thiery, Jean Paul 
Dahl, Olav
Lorens, James B.
Tronstad, Karl Johan
Røsland, G.V.
Keywords: DCA
Ionizing radiation
Warburg effect
Issue Date: 24-Feb-2021
Publisher: MDPI AG
Citation: Dyrstad, Sissel E., Lotsberg, Maria L., Tan, Tuan Zea, Pettersen, Ina K. N., Hjellbrekke, Silje, Tusubira, Deusdedit, Engelsen, Agnete S. T., Daubon, Thomas, Mourier, Arnaud, Thiery, Jean Paul, Dahl, Olav, Lorens, James B., Tronstad, Karl Johan, Røsland, G.V. (2021-02-24). 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. Cancers 13 (5) : 1-28. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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 har-boring 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 pro-duced 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Source Title: Cancers
ISSN: 2072-6694
DOI: 10.3390/cancers13050941
Rights: Attribution 4.0 International
Appears in Collections:Elements
Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_3390_cancers13050941.pdf9.72 MBAdobe PDF



Google ScholarTM



This item is licensed under a Creative Commons License Creative Commons