2. Academic Validation
  3. Berzosertib enhances the sensitivity of pediatric diffuse midline glioma H3K27-altered cells to radiotherapy

Berzosertib enhances the sensitivity of pediatric diffuse midline glioma H3K27-altered cells to radiotherapy

  • Cell Death Dis. 2026 Mar 20;17(1):331. doi: 10.1038/s41419-026-08567-7.
Nikita Gorainow 1,  Felix Sander 2,  Daniel Picard 2 3 4,  Marvin Christopher Frölich 1,  Katharina Eul 1,  Sarah Etemadi Afshar 1,  Julia Asche 1,  Michelle Monje 5,  Eric Raabe 6,  Jasmin Bartl 2,  Arndt Borkhardt 2,  Guido Reifenberger 3,  Nicole Dünker 7,  Maike Busch 7,  David Pauck 3,  Nan Qin 8 9,  Johann Matschke # 10 11,  Marc Remke # 2 3 4,  Verena Jendrossek # 12 13 14
Affiliations

Affiliations

  • 1 Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital Essen, Essen, Germany.
  • 2 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 3 Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 4 Department of Pediatric Hematology and Oncology, University Medical Center of Saarland, Saarland University, Homburg, Germany.
  • 5 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • 6 Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
  • 7 Center for Translational Neuro- and Behavioral Sciences, Institute of Anatomy II, Department of Neuroanatomy, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
  • 8 Department of Hematology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 9 Spatial & Functional Screening Core Facility, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
  • 10 Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital Essen, Essen, Germany. [email protected].
  • 11 German Cancer Consortium (DKTK) partner site Essen, a partnership between DKFZ and University Hospital Essen, Essen, Germany. [email protected].
  • 12 Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital Essen, Essen, Germany. [email protected].
  • 13 German Cancer Consortium (DKTK) partner site Essen, a partnership between DKFZ and University Hospital Essen, Essen, Germany. [email protected].
  • 14 West German Comprehensive Cancer Center Essen (CCC-WTZ), Essen, Germany. [email protected].
  • # Contributed equally.
PMID: 41862449 DOI: 10.1038/s41419-026-08567-7
Abstract

Diffuse midline glioma H3K27M-altered (DMG) remains a fatal pediatric brain Cancer driven by a global loss of histone H3K27 trimethylation. Radiotherapy comprises the most important treatment modality and significantly improves overall survival. Novel therapeutic strategies for DMG patients without or with radiotherapy are urgently needed. Here, we aimed to gain insights into potential radiation response modulators. To identify modulators of radiation response, we performed a high-throughput drug screening (HTS) in seven representative DMG cell lines using conventional chemotherapeutic drugs and phase I-IV drugs (n = 687), followed by irradiation with 0 or 2 × 4 Gray (Gy). The ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib emerged as a potent radiosensitizer. Its effects were validated in three DMG cell lines using short-term proliferation assays, long-term limiting dilution assays (LDA), 3D spheroid cultures, and the chorioallantoic membrane (CAM) assay in ovo. Across all three tested DMG cell line models, berzosertib enhanced the antineoplastic effects of clinically relevant radiation doses, significantly reducing proliferation and clonogenic survival, delaying spheroid growth, and suppressing tumor formation in ovo. These findings provide strong preclinical evidence that ATR inhibition increases the sensitivity of DMG cells to radiotherapy. They highlight a novel therapeutic vulnerability and support further exploration of ATR inhibitors in rational combination strategies to improve radiotherapy efficacy for this deadly disease.

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