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dc.contributor.authorAnderhub, SJ
dc.contributor.authorMak, GW-Y
dc.contributor.authorGurden, MD
dc.contributor.authorFaisal, A
dc.contributor.authorDrosopoulos, K
dc.contributor.authorWalsh, K
dc.contributor.authorWoodward, HL
dc.contributor.authorInnocenti, P
dc.contributor.authorWestwood, IM
dc.contributor.authorNaud, S
dc.contributor.authorHayes, A
dc.contributor.authorTheofani, E
dc.contributor.authorFilosto, S
dc.contributor.authorSaville, H
dc.contributor.authorBurke, R
dc.contributor.authorvan Montfort, RLM
dc.contributor.authorRaynaud, FI
dc.contributor.authorBlagg, J
dc.contributor.authorHoelder, S
dc.contributor.authorEccles, SA
dc.contributor.authorLinardopoulos, S
dc.date.accessioned2019-10-09T10:09:26Z
dc.date.issued2019-10
dc.identifier.citationMolecular cancer therapeutics, 2019, 18 (10), pp. 1696 - 1707
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3376
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.mct-18-1203
dc.description.abstractBOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel.
dc.formatPrint
dc.format.extent1696 - 1707
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectChromosomes, Human
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectPaclitaxel
dc.subjectTriazoles
dc.subjectPyrimidines
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectCell Cycle Proteins
dc.subjectCell Cycle
dc.subjectChromosome Segregation
dc.subjectCell Proliferation
dc.subjectBiological Availability
dc.subjectDrug Synergism
dc.subjectPTEN Phosphohydrolase
dc.subjectProtein-Tyrosine Kinases
dc.subjectCell Cycle Checkpoints
dc.subjectSpindle Apparatus
dc.subjectTriple Negative Breast Neoplasms
dc.titleHigh Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.
dc.typeJournal Article
dcterms.dateAccepted2019-07-01
rioxxterms.versionofrecord10.1158/1535-7163.mct-18-1203
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue10
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublished
pubs.volume18
pubs.embargo.termsNot known
icr.researchteamDrug Target Discoveryen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorLinardopoulos, Spyridonen
dc.contributor.icrauthorDrosopoulos, Konstantinosen
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorBurke, Rosemaryen
dc.contributor.icrauthorVan Montfort, Roberten


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Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0