دورية أكاديمية
High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.
| العنوان: | High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers. |
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| المؤلفون: | Anderhub SJ; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Mak GW; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Gurden MD; The Breast Cancer Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Faisal A; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Drosopoulos K; The Breast Cancer Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Walsh K; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Woodward HL; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Innocenti P; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Westwood IM; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Naud S; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Hayes A; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Theofani E; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Filosto S; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Saville H; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Burke R; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., van Montfort RLM; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Raynaud FI; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Blagg J; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Hoelder S; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Eccles SA; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom., Linardopoulos S; Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom. spiros.linardopoulos@icr.ac.uk.; The Breast Cancer Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2019 Oct; Vol. 18 (10), pp. 1696-1707. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Cell Cycle Checkpoints*/drug effects, Pyrimidines/*pharmacology , Spindle Apparatus/*metabolism , Triazoles/*pharmacology , Triple Negative Breast Neoplasms/*pathology, Animals ; Biological Availability ; Cell Cycle/drug effects ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromosome Segregation/drug effects ; Chromosomes, Human/genetics ; Drug Synergism ; Humans ; Mice ; PTEN Phosphohydrolase/metabolism ; Paclitaxel/pharmacology ; Paclitaxel/therapeutic use ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/metabolism ; Pyrimidines/chemistry ; Spindle Apparatus/drug effects ; Triazoles/chemistry ; Triple Negative Breast Neoplasms/drug therapy |
| مستخلص: | BOS172722 (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. (©2019 American Association for Cancer Research.) |
| معلومات مُعتمدة: | 22897 United Kingdom CRUK_ Cancer Research UK; C309/A11566 United Kingdom CRUK_ Cancer Research UK |
| المشرفين على المادة: | 0 (BOS172722) 0 (Cell Cycle Proteins) 0 (Pyrimidines) 0 (Triazoles) EC 2.7.10.1 (Protein-Tyrosine Kinases) EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 2.7.12.1 (TTK protein, human) EC 3.1.3.67 (PTEN Phosphohydrolase) P88XT4IS4D (Paclitaxel) |
| تواريخ الأحداث: | Date Created: 20191003 Date Completed: 20200609 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| DOI: | 10.1158/1535-7163.MCT-18-1203 |
| PMID: | 31575759 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
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| DOI: | 10.1158/1535-7163.MCT-18-1203 |