TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)

Abstract

Purpose: 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. Experimental Design: We assessed in vitro response to ionizing radiations in 13 different DIPG cellular models derived from treatment-na€ ve 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. Results: We uncover TP53 mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of TP53 WT DIPG cells with or without TP53 knockdown. In an integrated clinical, radiological, and molecular study, we show that TP53 MUT DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53 WT counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in TP53 MUT cells. Conclusions: 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.

Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG

“…Strikingly, DIPG patients with TP53 mutations were found to have a worse clinical and radiological response to radiation treatment compared to DIPG patients with wild-type TP53. TP53 mutant patients also showed a shorter time to relapse after radiation treatment compared to the patients with wild-type TP53, and a worse overall prognosis [24]. Therefore, therapeutic targeting of mutant p53 is expected to improve the radiation sensitivities of DIPG tumors with mutant TP53 status.…”

“…Indeed, molecular targeting of the H3 K27M epigenetic pathway with Jumonji family histone demethylase inhibitor GSK-J4 had been shown to decrease the viability of H3K27M tumor cells in vitro, and also reduced tumor growth in vivo in an orthotopic xenograft animal model. Furthermore, mutations in TP53 tumor suppressor gene were recently found to be a major driver of DIPG radio-resistance in patients, as well as in DIPG cell models, derived from treatment-naïve stereotactic biopsies [24]. Strikingly, DIPG patients with TP53 mutations were found to have a worse clinical and radiological response to radiation treatment compared to DIPG patients with wild-type TP53.…”

Tumor genotype dictates radiosensitization after Atm deletion in brainstem gliomas

“…Therefore, small molecule drugs that interfere with the DNA damage response represent a promising strategy for enhancing the ability of radiotherapy to kill cancer cells (4). Furthermore, a recent RNAi screen in patient-derived DIPG cells identified several kinases involved in the DNA-damage response whose inhibition selectively impaired survival following radiation exposure (5). One such kinase, Ataxia Telangiectasia Mutated (ATM) is recruited to sites of damage and activated through autophosphorylation (6)(7)(8).…”

Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG

“…Strikingly, DIPG patients with TP53 mutations were found to have a worse clinical and radiological response to radiation treatment compared to DIPG patients with wild-type TP53. TP53 mutant patients also showed a shorter time to relapse after radiation treatment compared to the patients with wild-type TP53, and a worse overall prognosis(23). Therefore, therapeutic targeting of mutant p53 is expected to improve radiation sensitivities of DIPG tumors with mutant TP53 status.…”

“…Indeed, molecular targeting of the H3 K27M epigenetic pathway with Jumonji family histone demethylase inhibitor GSK-J4 had been shown to decrease viability of H3K27M tumor cells in vitro, and also reduced tumor growth in vivo in an orthotopic xenograft animal model. Furthermore, mutations in TP53 tumor suppressor gene were recently found to be a major driver of DIPG radio-resistance in patients, as well as in DIPG cell models, derived from treatment-naïve stereotactic biopsies(23). Strikingly, DIPG patients with TP53 mutations were found to have a worse clinical and radiological response to radiation treatment compared to DIPG patients with wild-type TP53.…”