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dc.contributor.authorAnderhub, SJen_US
dc.contributor.authorMak, GW-Yen_US
dc.contributor.authorGurden, MDen_US
dc.contributor.authorFaisal, Aen_US
dc.contributor.authorDrosopoulos, Ken_US
dc.contributor.authorWalsh, Ken_US
dc.contributor.authorWoodward, HLen_US
dc.contributor.authorInnocenti, Pen_US
dc.contributor.authorWestwood, IMen_US
dc.contributor.authorNaud, Sen_US
dc.contributor.authorHayes, Aen_US
dc.contributor.authorTheofani, Een_US
dc.contributor.authorFilosto, Sen_US
dc.contributor.authorSaville, Hen_US
dc.contributor.authorBurke, Ren_US
dc.contributor.authorvan Montfort, RLMen_US
dc.contributor.authorRaynaud, FIen_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorHoelder, Sen_US
dc.contributor.authorEccles, SAen_US
dc.contributor.authorLinardopoulos, Sen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-10-09T10:09:26Z
dc.date.issued2019-10en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/31575759en_US
dc.identifier18/10/1696en_US
dc.identifier.citationMol Cancer Ther, 2019, 18 (10), pp. 1696 - 1707en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3376
dc.identifier.eissn1538-8514en_US
dc.identifier.doi10.1158/1535-7163.MCT-18-1203en_US
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.en_US
dc.format.extent1696 - 1707en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleHigh Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-07-01en_US
rioxxterms.versionofrecord10.1158/1535-7163.MCT-18-1203en_US
rioxxterms.licenseref.startdate2019-10en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMol Cancer Theren_US
pubs.issue10en_US
pubs.notesNot knownen_US
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/Drug Target Discovery
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-statusPublisheden_US
pubs.volume18en_US
pubs.embargo.termsNot knownen_US
icr.researchteamDrug Target Discoveryen_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorVan Montfort, Roberten_US
dc.contributor.icrauthorLinardopoulos, Spyridonen_US
dc.contributor.icrauthorDrosopoulos, Konstantinosen_US


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