Browsing by Author "Yang, Yanzhu"

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    Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy
    (AACR, 2019-12) Du, Jian; Yan, Lei; Torres, Raquel; Gong, Xueqian; Bian, Huimin; Marugán, Carlos; Boehnke, Karsten; Baquero, Carmen; Hui, Yu-Hua; Chapman, Sonya C.; Yang, Yanzhu; Zeng, Yi; Bogner, Sarah M.; Foreman, Robert T.; Capen, Andrew; Donoho, Gregory P.; Van Horn, Robert D.; Barnard, Darlene S.; Dempsey, Jack A.; Beckmann, Richard P.; Marshall, Mark S.; Chio, Li-Chun; Qian, Yuewei; Webster, Yue W.; Aggarwal, Amit; Chu, Shaoyou; Bhattachar, Shobha; Stancato, Louis F.; Dowless, Michele S.; Iversen, Phillip W.; Manro, Jason R.; Walgren, Jennie L.; Halstead, Bartley W.; Dieter, Matthew Z.; Martinez, Ricardo; Bhagwat, Shripad V.; Kreklau, Emiko L.; Lallena, Maria Jose; Ye, Xiang S.; Patel, Bharvin K. R.; Reinhard, Christoph; Plowman, Gregory D.; Barda, David A.; Henry, James R.; Buchanan, Sean G.; Campbell, Robert M.; Pediatrics, School of Medicine
    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.
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    The tumor suppressor CDKN3 controls mitosis
    (Rockefeller University Press, 2013) Nalepa, Grzegorz; Barnholtz-Sloan, Jill; Enzor, Rikki; Dey, Dilip; He, Ying; Gehlhausen, Jeff R.; Lehmann, Amalia S.; Park, Su-Jung; Yang, Yanzhu; Yang, Xianlin; Chen, Shi; Guan, Xiaowei; Chen, Yanwen; Renbarger, Jamie; Yang, Feng-Chun; Parada, Luis F.; Clapp, Wade; Pediatrics, School of Medicine
    Mitosis is controlled by a network of kinases and phosphatases. We screened a library of small interfering RNAs against a genome-wide set of phosphatases to comprehensively evaluate the role of human phosphatases in mitosis. We found four candidate spindle checkpoint phosphatases, including the tumor suppressor CDKN3. We show that CDKN3 is essential for normal mitosis and G1/S transition. We demonstrate that subcellular localization of CDKN3 changes throughout the cell cycle. We show that CDKN3 dephosphorylates threonine-161 of CDC2 during mitotic exit and we visualize CDC2(pThr-161) at kinetochores and centrosomes in early mitosis. We performed a phosphokinome-wide mass spectrometry screen to find effectors of the CDKN3-CDC2 signaling axis. We found that one of the identified downstream phosphotargets, CKβ phosphorylated at serine 209, localizes to mitotic centrosomes and controls the spindle checkpoint. Finally, we show that CDKN3 protein is down-regulated in brain tumors. Our findings indicate that CDKN3 controls mitosis through the CDC2 signaling axis. These results have implications for targeted anticancer therapeutics.