Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy
| Autor: | Xueqian Gong, Karsten Boehnke, Carmen Baquero, Yue-Wei Qian, Gregory P. Donoho, Jason Manro, Robert T. Foreman, Carlos Marugán, Sonya C. Chapman, Yi Zeng, Phillip W Iversen, Jack A. Dempsey, Matthew Z. Dieter, David Anthony Barda, Henry James Robert, Michele Dowless, Shripad V. Bhagwat, Robert M. Campbell, Andrew Capen, Robert D. Van Horn, Amit Aggarwal, Mark S. Marshall, Darlene S. Barnard, Bharvin K. R. Patel, Louis Stancato, Huimin Bian, Li-Chun Chio, Sean Buchanan, Jian Du, Richard P. Beckmann, Christoph Reinhard, Ricardo Martinez, Gregory D. Plowman, Lei Yan, Shobha N. Bhattachar, Sarah M. Bogner, Maria Jose Lallena, Xiang S. Ye, Jennie L. Walgren, Yu-Hua Hui, Yue Webster, Emiko L. Kreklau, Raquel Torres, Yanzhu Yang, Bartley W. Halstead, Shaoyou Chu |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Aurora inhibitor Aurora B kinase Mitosis Antineoplastic Agents Apoptosis macromolecular substances Biology 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans Kinase activity Aurora Kinase A Cell Proliferation Cancer medicine.disease Spindle apparatus enzymes and coenzymes (carbohydrates) 030104 developmental biology Oncology 030220 oncology & carcinogenesis embryonic structures Cancer cell Cancer research Female biological phenomena cell phenomena and immunity Cytokinesis HeLa Cells |
| Zdroj: | Molecular Cancer Therapeutics. 18:2207-2219 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-18-0529 |
| Popis: | Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform–selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A–selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition–associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A–selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent. |
| Databáze: | OpenAIRE |
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