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dc.contributor.authorSriskandarajah, P
dc.contributor.authorDe Haven Brandon, A
dc.contributor.authorMacLeod, K
dc.contributor.authorCarragher, NO
dc.contributor.authorKirkin, V
dc.contributor.authorKaiser, M
dc.contributor.authorWhittaker, SR
dc.date.accessioned2020-05-22T14:13:14Z
dc.date.issued2020-03-30
dc.identifier.citationBMC cancer, 2020, 20 (1), pp. 269 - ?
dc.identifier.issn1471-2407
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3628
dc.identifier.eissn1471-2407
dc.identifier.doi10.1186/s12885-020-06735-2
dc.description.abstractBACKGROUND: Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RAS-mutant MM. METHODS: The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time. RESULTS: The Tra/Dex combination demonstrated synergistic cytotoxicity in KRASG12A mutant lines MM.1S and RPMI-8226. The induction of apoptosis was associated with decreased MCL-1 expression and increased BIM expression. Reverse phase proteomic arrays revealed suppression of FAK, PYK2, FLT3, NDRG1 and 4EBP1 phosphorylation with the Tra/Dex combination. Notably, NDRG1 expression was associated with the synergistic response to Tra/Dex. MM cells were sensitive to PDK1 inhibition and IGF1-induced signalling partially protected from Tra/Dex treatment, highlighting the importance of this pathway. In the MM.1S tumor xenograft model, only the combination of Tra/Dex resulted in a significant inhibition of tumor growth. CONCLUSIONS: Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM.
dc.formatElectronic
dc.format.extent269 - ?
dc.languageeng
dc.language.isoeng
dc.publisherBMC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectMultiple Myeloma
dc.subjectPyridones
dc.subjectPyrimidinones
dc.subjectDexamethasone
dc.subjectras Proteins
dc.subjectMAP Kinase Kinase Kinases
dc.subjectIntracellular Signaling Peptides and Proteins
dc.subjectCell Cycle Proteins
dc.subjectReceptors, Glucocorticoid
dc.subjectAntineoplastic Agents
dc.subjectDrug Therapy, Combination
dc.subjectSignal Transduction
dc.subjectApoptosis
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDrug Synergism
dc.subjectMutation
dc.subjectPyruvate Dehydrogenase Acetyl-Transferring Kinase
dc.titleCombined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma.
dc.typeJournal Article
dcterms.dateAccepted2020-03-11
rioxxterms.versionofrecord10.1186/s12885-020-06735-2
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-03-30
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBMC cancer
pubs.issue1
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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Drug Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Myeloma Group
pubs.publication-statusPublished
pubs.volume20
pubs.embargo.termsNot known
icr.researchteamCancer Pharmacology & Stress Response (CPSR)
icr.researchteamMolecular Drug Resistance
icr.researchteamMyeloma Group
dc.contributor.icrauthorSriskandarajah, Priya
dc.contributor.icrauthorKirkin, Vladimir
dc.contributor.icrauthorKaiser, Martin


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