Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Clinical cancer research, 2019-11, Vol.25 (22), p.6788-6800
Ort / Verlag
United States: American Association for Cancer Research
Erscheinungsjahr
2019
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG.
We assessed
response to ionizing radiations in 13 different DIPG cellular models derived from treatment-naïve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize DIPG cells to ionizing radiations.
We uncover
mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of
DIPG cells with or without
knockdown. In an integrated clinical, radiological, and molecular study, we show that
DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their
counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in
cells.
Here, we demonstrate that
mutations are driving DIPG radioresistance both in patients and corresponding cellular models. We suggest alternative treatment strategies to mitigate radioresistance with CHK1 inhibitors. These findings will allow to consequently refine radiotherapy schedules in DIPG.