TY - JOUR
T1 - WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas
AU - Caretti, Viola
AU - Hiddingh, Lotte
AU - Lagerweij, Tonny
AU - Schellen, Pepijn
AU - Koken, Phil W.
AU - Hulleman, Esther
AU - van Vuurden, Dannis G.
AU - Vandertop, W. Peter
AU - Kaspers, Gertjan J. L.
AU - Noske, David P.
AU - Wurdinger, Thomas
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
U2 - https://doi.org/10.1158/1535-7163.MCT-12-0735
DO - https://doi.org/10.1158/1535-7163.MCT-12-0735
M3 - Article
C2 - 23270927
SN - 1535-7163
VL - 12
SP - 141
EP - 150
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 2
ER -