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|Ref Type||Journal Article|
|Authors||Anderhub SJ, Mak GW, Gurden MD, Faisal A, Drosopoulos K, Walsh K, Woodward HL, Innocenti P, Westwood IM, Naud S, Hayes A, Theofani E, Filosto S, Saville H, Burke R, van Montfort RLM, Raynaud FI, Blagg J, Hoelder S, Eccles SA, Linardopoulos S|
|Title||High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|BOS172722||CCT289346|BOS-172722|BOS 172722||MPS1 Inhibitor 25||BOS172722 inhibits MPS1 (TTK), potentially resulting in increased tumor cell death and decreased tumor growth (PMID: 31575759).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||BOS172722 + Paclitaxel||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, BOS172722 and Taxol (paclitaxel) demonstrated synergy in triple-negative breast cancer (TNBC) cell lines in culture, resulting in increased cell death, and the combination of BOS172722 and Taxol (paclitaxel) induced tumor regression in TNBC cell line and patient-derived xenograft (PDX) models, and decreased tumor growth and increased survival in a TNBC cell line xenograft metastasis model, demonstrating increased benefit over Taxol (paclitaxel) or BOS172722 alone (PMID: 31575759).||31575759|
|Unknown unknown||lung cancer||not applicable||BOS172722||Preclinical - Cell culture||Actionable||In a preclinical study, lung cancer cell lines demonstrated sensitivity to growth inhibition by BOS172722 in culture (PMID: 31575759).||31575759|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||BOS172722||Preclinical - Cell line xenograft||Actionable||In a preclinical study, triple-negative breast cancer (TNBC) cell lines demonstrated increased sensitivity to BOS172722 compared to non-triple-negative breast cancer cell lines in culture, and BOS172722 treatment resulted in moderate tumor growth inhibition in a TNBC cell line xenograft model (PMID: 31575759).||31575759|
|Unknown unknown||colon cancer||not applicable||BOS172722||Preclinical - Cell culture||Actionable||In a preclinical study, BOS172722 treatment resulted in increased apoptosis and decreased growth of a colon cancer cell line in culture (PMID: 31575759).||31575759|