WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas

Viola Caretti, Lotte Hiddingh, Tonny Lagerweij, Pepijn Schellen, Phil W. Koken, Esther Hulleman, Dannis van Vuurden, William P. Vandertop, Gertjan J.L. Kaspers, David P. Noske, Thomas Wurdinger

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)141-150
TijdschriftMolecular Cancer Therapeutics
Volume12
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - feb. 2013

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