title: WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas.
abstract: Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric disease. Thus far, no therapeutic agent has proven beneficial in the treatment of this malignancy. Therefore, conventional DNA-damaging radiotherapy remains the standard treatment, providing transient neurologic improvement without improving the probability of overall survival. During radiotherapy, WEE1 kinase controls the G(2) cell-cycle checkpoint, allowing for repair of irradiation (IR)-induced DNA damage. Here, we show that WEE1 kinase is one of the highest overexpressed kinases in primary DIPG tissues compared with matching non-neoplastic brain tissues. Inhibition of WEE1 by MK-1775 treatment of DIPG cells inhibited the IR-induced WEE1-mediated phosphorylation of CDC2, resulting in reduced G(2)-M arrest and decreased cell viability. Finally, we show that MK-1775 enhances the radiation response of E98-Fluc-mCherry DIPG mouse xenografts. Altogether, these results show that inhibition of WEE1 kinase in conjunction with radiotherapy holds potential as a therapeutic approach for the treatment of DIPG.
authors.affiliation: Departments of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Viola
authors.initials: V
authors.lastname: Caretti
authors.forename: Lotte
authors.initials: L
authors.lastname: Hiddingh
authors.forename: Tonny
authors.initials: T
authors.lastname: Lagerweij
authors.forename: Pepijn
authors.initials: P
authors.lastname: Schellen
authors.forename: Phil W
authors.initials: PW
authors.lastname: Koken
authors.forename: Esther
authors.initials: E
authors.lastname: Hulleman
authors.forename: Dannis G
authors.initials: DG
authors.lastname: van Vuurden
authors.forename: W Peter
authors.initials: WP
authors.lastname: Vandertop
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: David P
authors.initials: DP
authors.lastname: Noske
authors.forename: Thomas
authors.initials: T
authors.lastname: Wurdinger
mesh_terms: D000818:Animals; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D003131:Combined Modality Therapy; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011838:Radiation-Sensitizing Agents; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse; C549567:adavosertib