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dc.contributor.authorDelgado-Goni, T
dc.contributor.authorMiniotis, MF
dc.contributor.authorWantuch, S
dc.contributor.authorParkes, HG
dc.contributor.authorMarais, R
dc.contributor.authorWorkman, P
dc.contributor.authorLeach, MO
dc.contributor.authorBeloueche-Babari, M
dc.date.accessioned2016-11-23T12:58:13Z
dc.date.issued2016-12
dc.identifier.citationMolecular cancer therapeutics, 2016, 15 (12), pp. 2987 - 2999
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/246
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.mct-16-0068
dc.description.abstractUnderstanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long-term disease control. This work investigates the downstream metabolic consequences of BRAF inhibition with vemurafenib, the molecular and biochemical processes that underpin them, their significance for antineoplastic activity, and potential as noninvasive imaging response biomarkers. 1 H NMR spectroscopy showed that vemurafenib decreases the glycolytic activity of BRAF-mutant (WM266.4 and SKMEL28) but not BRAF WT (CHL-1 and D04) human melanoma cells. In WM266.4 cells, this was associated with increased acetate, glycine, and myo-inositol levels and decreased fatty acyl signals, while the bioenergetic status was maintained. 13 C NMR metabolic flux analysis of treated WM266.4 cells revealed inhibition of de novo lactate synthesis and glucose utilization, associated with increased oxidative and anaplerotic pyruvate carboxylase mitochondrial metabolism and decreased lipid synthesis. This metabolic shift was associated with depletion of hexokinase 2, acyl-CoA dehydrogenase 9, 3-phosphoglycerate dehydrogenase, and monocarboxylate transporters (MCT) 1 and 4 in BRAF-mutant but not BRAF WT cells and, interestingly, decreased BRAF-mutant cell dependency on glucose and glutamine for growth. Further, the reduction in MCT1 expression observed led to inhibition of hyperpolarized 13 C-pyruvate-lactate exchange, a parameter that is translatable to in vivo imaging studies, in live WM266.4 cells. In conclusion, our data provide new insights into the molecular and metabolic consequences of BRAF inhibition in BRAF-driven human melanoma cells that may have potential for combinatorial therapeutic targeting as well as noninvasive imaging of response. Mol Cancer Ther; 15(12); 2987-99. ©2016 AACR.
dc.formatPrint-Electronic
dc.format.extent2987 - 2999
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectMitochondria
dc.subjectHumans
dc.subjectMelanoma
dc.subjectSulfonamides
dc.subjectLactates
dc.subjectPyruvic Acid
dc.subjectIndoles
dc.subjectPyruvate Carboxylase
dc.subjectProto-Oncogene Proteins B-raf
dc.subjectGlucose
dc.subjectAntineoplastic Agents
dc.subjectGene Expression Regulation, Enzymologic
dc.subjectEnergy Metabolism
dc.subjectMutation
dc.subjectModels, Biological
dc.subjectMetabolomics
dc.subjectVemurafenib
dc.titleThe BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate-Lactate Exchange in BRAF-Mutant Human Melanoma Cells.
dc.typeJournal Article
dcterms.dateAccepted2016-09-24
rioxxterms.versionofrecord10.1158/1535-7163.mct-16-0068
rioxxterms.licenseref.startdate2016-12
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue12
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Magnetic Resonance
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Magnetic Resonance
pubs.publication-statusPublished
pubs.volume15
pubs.embargo.termsNot known
icr.researchteamMagnetic Resonanceen_US
dc.contributor.icrauthorBeloueche-Babari, Mouniaen
dc.contributor.icrauthorDelgado-Goni, Teresaen
dc.contributor.icrauthorParkes, Harolden
dc.contributor.icrauthorLeach, Martinen
dc.contributor.icrauthorWorkman, Paulen


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