title: In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma.
abstract: Kinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G(2) checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G(2) arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma.
authors.affiliation: Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, VU University Medical Center, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Shahryar E
authors.initials: SE
authors.lastname: Mir
authors.forename: Philip C
authors.initials: PC
authors.lastname: De Witt Hamer
authors.forename: Przemek M
authors.initials: PM
authors.lastname: Krawczyk
authors.forename: Leonora
authors.initials: L
authors.lastname: Balaj
authors.forename: An
authors.initials: A
authors.lastname: Claes
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Niers
authors.forename: Angela A G
authors.initials: AA
authors.lastname: Van Tilborg
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: W
authors.initials: W
authors.lastname: Peter Vandertop
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Aten
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: Van Noorden
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
mesh_terms: D054458:Amplified Fragment Length Polymorphism Analysis; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D016195:G2 Phase / Q000502:physiology; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C440869:PD 0166285; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human