Targeting Mitosis in Cancer: Emerging Strategies

Mol Cell. 2015 Nov 19;60(4):524-36. doi: 10.1016/j.molcel.2015.11.006.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Aurora Kinase A / antagonists & inhibitors
  • Cell Cycle Proteins / antagonists & inhibitors
  • Genomic Instability / drug effects
  • Humans
  • Mitosis / drug effects*
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • PLK4 protein, human
  • Protein-Tyrosine Kinases
  • AURKA protein, human
  • Aurora Kinase A
  • Protein-Serine-Threonine Kinases
  • TTK protein, human