ArticleNeuro-oncology2023
ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma.
Article in Neuro-oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.
- Radiotherapy for High-Grade Gliomas in Adults and Children: A Systematic Review of Advances Published in the Second Half of 2023.International journal of molecular sciences · 2026Pooled it
- Exon-skipping antisense oligonucleotides for H3.3K27M-altered diffuse midline glioma therapy.Molecular therapy. Nucleic acids · 2026Article
- DNA-PKcs inhibition sensitizes glioblastoma to radiotherapy through reprogramming of tumor cell states and immune microenvironment cell types.Research square · 2026Article
- Targeted therapies in pediatric oncology: A start.Molecular therapy. Oncology · 2026Review
- Combined carbon ion radiotherapy and immunotherapy: leveraging the immunological advantages of carbon ion.Frontiers in immunology · 2026Review
- Research progress of DNA damage repair (DDR) and DDR inhibitors in tumor immunotherapy.World journal of surgical oncology · 2025Review
- Therapeutic Targeting of DNA Damage Response Pathways inBrain tumor research and treatment · 2025Review
- Germline-Somatic Interactions in BRCA-Associated Cancers: Unique Molecular Profiles and Clinical Outcomes Linking ATM to TP53 Synthetic Essentiality.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Perspectives on cancer therapy-synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges.Cell death discovery · 2025Review
- The Development of ATM Inhibitors in Cancer Therapy.Targeted oncology · 2025Review
- DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology.Neuro-oncology · 2024Review
- Review
- Targeting replication stress in glioblastoma: From genotoxic treatment and inhibitors of the DNA damage response to immunotherapy.Neuro-oncology advancesReview
Corrections and comments
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Authors and funding
24 authors at 1 institution in 1 country.
Funding
Abstract
backgroundPediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG has alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG.
methodsWe conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts.
resultsAZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic nonhomologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition.
conclusionsOur study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.