title: Targeting Mitosis in Cancer: Emerging Strategies.
abstract: The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic. This review briefly examines past cell-cycle-targeted therapeutics and outlines how experience with these agents has provided valuable insight to refine and improve anti-mitotic strategies. An overview of emerging anti-mitotic approaches with promising pre-clinical results is provided, and the concept of exploiting the genomic instability of tumor cells through therapeutic inhibition of mitotic checkpoints is discussed. We believe this strategy has a high likelihood of success given its potential to enhance therapeutic index by targeting tumor-specific vulnerabilities. This reasoning stimulated our development of novel inhibitors targeting the critical regulators of genomic stability and the mitotic checkpoint: AURKA, PLK4, and Mps1/TTK.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Dominguez-Brauer
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Heiko
authors.initials: H
authors.lastname: Blaser
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, ON M5G 2M9, Canada. Electronic address: tmak@uhnres.utoronto.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C490219:PLK4 protein, human; D011505:Protein-Tyrosine Kinases; C576917:AURKA protein, human; D064096:Aurora Kinase A; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human