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dc.contributor.authorVarshavi, Dorna
dc.contributor.authorVarshavi, Dorsa
dc.contributor.authorMcCarthy, Nicola
dc.contributor.authorVeselkov, Kirill
dc.contributor.authorKeun, Hector C
dc.contributor.authorEverett, Jeremy R
dc.date.accessioned2022-01-07T16:53:39Z
dc.date.available2022-01-07T16:53:39Z
dc.date.issued2021-11-25
dc.identifier.issn1573-3882
dc.identifier.otherPMC8616861
dc.identifier.other34822010
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332428
dc.description.abstractINTRODUCTION: KRAS was one of the earliest human oncogenes to be described and is one of the most commonly mutated genes in different human cancers, including colorectal cancer. Despite KRAS mutants being known driver mutations, KRAS has proved difficult to target therapeutically, necessitating a comprehensive understanding of the molecular mechanisms underlying KRAS-driven cellular transformation. OBJECTIVES: To investigate the metabolic signatures associated with single copy mutant KRAS in isogenic human colorectal cancer cells and to determine what metabolic pathways are affected. METHODS: Using NMR-based metabonomics, we compared wildtype (WT)-KRAS and mutant KRAS effects on cancer cell metabolism using metabolic profiling of the parental KRAS G13D/+ HCT116 cell line and its isogenic, derivative cell lines KRAS +/- and KRAS G13D/-. RESULTS: Mutation in the KRAS oncogene leads to a general metabolic remodelling to sustain growth and counter stress, including alterations in the metabolism of amino acids and enhanced glutathione biosynthesis. Additionally, we show that KRASG13D/+ and KRASG13D/- cells have a distinct metabolic profile characterized by dysregulation of TCA cycle, up-regulation of glycolysis and glutathione metabolism pathway as well as increased glutamine uptake and acetate utilization. CONCLUSIONS: Our study showed the effect of a single point mutation in one KRAS allele and KRAS allele loss in an isogenic genetic background, hence avoiding confounding genetic factors. Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1573-3890
dc.sourcenlmid: 101274889
dc.subjectCells
dc.subjectNMR
dc.subjectMutations
dc.subjectMetabolomics
dc.subjectmetabolic profiling
dc.subjectColorectal Cancer
dc.subjectMetabonomics
dc.subjectHCT116
dc.subjectKras
dc.titleMetabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines.
dc.typeArticle
dc.date.updated2022-01-07T16:53:38Z
prism.issueIdentifier12
prism.publicationNameMetabolomics
prism.volume17
dc.identifier.doi10.17863/CAM.79874
dcterms.dateAccepted2021-10-31
rioxxterms.versionofrecord10.1007/s11306-021-01852-w
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidEverett, Jeremy R [0000-0003-1550-4482]
dc.identifier.eissn1573-3890
cam.issuedOnline2021-11-25


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International