Evidence map›Paper›PMID 40562042›Full record

ArticleCell reports. Medicine2025

Targeting synthetic lethality between non-homologous end joining and radiation in very-high-risk medulloblastoma.

Alexandria DeCarlo, Graham MacLeod, Carolina Fernandes da Silva, Li Qing Shen, Julija Povilaikaite, Madeline Deane, Lucas Aragao, Mariska Sie, Deborah Termini, Jonathan Magee and 17 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports. Medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Article
  2. Article
  3. From developmental origins to relapse: molecular and therapeutic insights in medulloblastoma.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2026
    Review
  4. Article
  5. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

27 authors.

Alexandria DeCarloDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Graham MacLeodDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
Carolina Fernandes da SilvaDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Li Qing ShenDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Julija PovilaikaiteDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Madeline DeaneDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Lucas AragaoDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Mariska SieDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Deborah TerminiDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Jonathan MageeDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Brian GudenasCenter of Excellence in Neuro-Oncology Sciences (CENOS), Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Sneha SukumaranMontreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 1A1, Canada.
Frederic CharronMontreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 1A1, Canada; Department of Anatomy and Cell Biology and Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada.
Richard MarcellusDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
Rima Al-AwarDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
Ahmed AmanDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
Denis ReynaudSPARC BioCentre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Amarine TrolatSPARC BioCentre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Leanne Wybenga-GrootSPARC BioCentre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Uri TaboriDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G 1E8, Canada.
Carolina NörDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Shane M HardingDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Radiation Oncology and Immunology, University of Toronto, Toronto, ON M5T 1P5, Canada.
Michael F MoranSPARC BioCentre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Paul A NorthcottCenter of Excellence in Neuro-Oncology Sciences (CENOS), Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Peter DirksDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Stephane AngersDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada. Electronic address: stephane.angers@utoronto.ca.
Vijay RamaswamyDevelopmental, Stem Cell and Cancer Biology Programme, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G 1E8, Canada. Electronic address: vijay.ramaswamy@sickkids.ca.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Specific and biologically informed treatments for medulloblastoma, especially for the highly lethal TP53-mutant SHH subgroup, remain elusive, where radiotherapy is the primary treatment modality. Leveraging genome-wide CRISPR-Cas9 dropout screening in combination with lethal doses of radiotherapy, we identify loss of p53 as the main driver of radiation resistance in SHH medulloblastoma. A negative-selection CRISPR-Cas9 screen across multiple models of Trp53-deficient SHH medulloblastoma reveals a strong synthetic lethal interaction between components of the non-homologous end-joining pathway and radiation, particularly DNA-dependent protein kinase (DNA-PK) and its binding partners. Both genetic and pharmacological perturbation of DNA-PK enhance radiosensitivity in TP53-deficient SHH medulloblastoma, leading to cell death. In vivo treatment of both somatic and germline TP53-mutant SHH medulloblastoma models with peposertib, a small-molecule inhibitor of DNA-PK, significantly improves survival when combined with radiotherapy, strongly supporting further clinical investigation.

Indexed as

Cerebellar NeoplasmsDNA End-Joining RepairMedulloblastomaSynthetic Lethal MutationsAnimalsCell Line, TumorCRISPR-Cas SystemsDNA-Activated Protein KinaseHumansMiceRadiation ToleranceTumor Suppressor Protein p53DNA-Activated Protein KinaseTumor Suppressor Protein p53DNA-protein kinaseDNA repairmedulloblastomanon-homologous end joiningp53peposertibradiationsubgroup

Identifiers

PMID40562042
PMCPMC12281405

What OpenQuestion holds

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LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

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.