Please use this identifier to cite or link to this item: https://doi.org/10.3390/cancers13050941
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dc.titleBlocking 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
dc.contributor.authorDyrstad, Sissel E.
dc.contributor.authorLotsberg, Maria L.
dc.contributor.authorTan, Tuan Zea
dc.contributor.authorPettersen, Ina K. N.
dc.contributor.authorHjellbrekke, Silje
dc.contributor.authorTusubira, Deusdedit
dc.contributor.authorEngelsen, Agnete S. T.
dc.contributor.authorDaubon, Thomas
dc.contributor.authorMourier, Arnaud
dc.contributor.authorThiery, Jean Paul
dc.contributor.authorDahl, Olav
dc.contributor.authorLorens, James B.
dc.contributor.authorTronstad, Karl Johan
dc.contributor.authorRøsland, G.V.
dc.date.accessioned2022-10-13T07:54:47Z
dc.date.available2022-10-13T07:54:47Z
dc.date.issued2021-02-24
dc.identifier.citationDyrstad, 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. https://doi.org/10.3390/cancers13050941
dc.identifier.issn2072-6694
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/233232
dc.description.abstractIncreased 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.
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceScopus OA2021
dc.subjectDCA
dc.subjectEGFR TKI
dc.subjectGlycolysis
dc.subjectIonizing radiation
dc.subjectMitochondria
dc.subjectNSCLC
dc.subjectPDH
dc.subjectPDHK
dc.subjectWarburg effect
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentDEPT OF BIOCHEMISTRY
dc.description.doi10.3390/cancers13050941
dc.description.sourcetitleCancers
dc.description.volume13
dc.description.issue5
dc.description.page1-28
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