CHAPTER 6 WEE 1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric disease. Thus far no therapeutic agent has proven beneficial in the treatment of this malignancy. Hence, conventional DNA-damaging radiotherapy (RT) remains the standard treatment, providing transient neurological improvement without improving probability of overall survival. During RT, WEE1 kinase controls the G2 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 as compared to 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 G2/M arrest and decreased cell viability. Finally, we demonstrate 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 RT holds potential as a therapeutic approach for the treatment of DIPG.