WEE1 Kinase Inhibition Enhances the Radiation Response of Diffuse Intrinsic Pontine Gliomas

• DOI: 10.1158/1535-7163.mct-12-0735
• Publication Date: 2012-12-28T04:27:30Z
• Authors: Viola Caretti; Lotte Hiddingh; Tonny Lagerweij; Pepijn Schellen; Phil W. Koken; Esther Hulleman; Dannis G. van Vuu...; W. Peter Vandertop; Gertjan J.L. Kaspers; David P. Noske; Thomas Wurdinger
• Keywords: Wee1; Radiation sensitivity

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 standard treatment, providing transient neurologic improvement without improving probability overall survival. During radiotherapy, WEE1 kinase controls G(2) cell-cycle checkpoint, allowing for repair irradiation (IR)-induced DNA damage. Here, we show that one highest overexpressed kinases primary DIPG tissues compared with matching non-neoplastic brain tissues. Inhibition by MK-1775 cells inhibited IR-induced WEE1-mediated phosphorylation CDC2, resulting reduced G(2)-M arrest and decreased cell viability. Finally, enhances radiation response E98-Fluc-mCherry mouse xenografts. Altogether, these results inhibition conjunction holds potential as approach DIPG.