title: WEE1 inhibition and genomic instability in cancer.
abstract: One of the hallmarks of cancer is genomic instability controlled by cell cycle checkpoints. The G1 and G2 checkpoints allow DNA damage responses, whereas the mitotic checkpoint enables correct seggregation of the sister chromosomes to prevent aneuploidy. Cancer cells often lack a functional G1 arrest and rely on G2 arrest for DNA damage responses. WEE1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancer types. Inhibition of WEE1 is a promising strategy in cancer therapy in combination with DNA-damaging agents, especially when cancer cells harbor p53 mutations, as it causes mitotic catastrophy when DNA is not repaired during G2 arrest. Cancer cell response to WEE1 inhibition monotherapy has also been demonstrated in various types of cancer, including p53 wild-type cancers. We postulate that chromosomal instability can explain tumor response to WEE1 monotherapy. Therefore, chromosomal instability may need to be taken into account when determining the most effective strategy for the use of WEE1 inhibitors in cancer therapy.
authors.affiliation: Neurosurgical Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lianne E M
authors.initials: LE
authors.lastname: Vriend
authors.forename: Philip C
authors.initials: PC
authors.lastname: De Witt Hamer
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: Van Noorden
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C499348:Wee1 protein, mouse
keywords: Cancer; Cell cycle checkpoint; Chromosomal instability; Genomic instability; WEE1 kinase; p53