Abstract
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 in vitro 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 TP53 mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of TP53WT DIPG cells with or without TP53 knockdown. In an integrated clinical, radiological, and molecular study, we show that TP53MUT DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53WT counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in TP53MUT cells. Here, we demonstrate that TP53 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.
Highlights
Brain tumors represent the first cause of death from cancer in children, adolescents, and young adults
Radiological, and molecular study, we show that TP53MUT Diffuse intrinsic pontine gliomas (DIPG) patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53WT counterparts
Here, we demonstrate that TP53 mutations are driving DIPG radioresistance both in patients and corresponding cellular models
Summary
Brain tumors represent the first cause of death from cancer in children, adolescents, and young adults. High-grade gliomas are the most frequent and aggressive forms. Diffuse intrinsic pontine gliomas (DIPG) are the most severe of these high-grade gliomas and have been recently associated with other diffuse midline gliomas sharing the same driving histone H3-K27M mutation [1]. Since the discovery of the effect of radiotherapy (RT) on brainstem tumors [2], this therapeutic modality has remained the only validated treatment for DIPG. This usually consists in threedimensional conformal photon-based RT to a range of 54 to 59.4 Gy given in 30 to 33 fractions of 1.8 Gy daily [3]. Resistance to standard chemotherapy has been well demonstrated in vitro in DIPG cells derived from both diagnostic and autopsy samples [7, 8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
