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Ref Type Journal Article
PMID (31575759)
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
Vol 18
Issue 10
Date 2019 10
URL
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.

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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 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 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
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 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 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