Targeting synthetic lethality between non-homologous end joining and radiation in very-high-risk medulloblastoma
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.
Authors
- Michael F. Moran (ORCID: https://orcid.org/0000-0003-4878-9285)
- Uri Tabori (ORCID: https://orcid.org/0000-0002-5019-2683)
- Graham MacLeod (ORCID: https://orcid.org/0000-0001-6401-9307)
- Mariska Sie
- Julija Povilaikaite
- Alexandria DeCarlo
- Carolina Fernandes da Silva (ORCID: https://orcid.org/0000-0003-0026-1318)
- Rima Al‐awar (ORCID: https://orcid.org/0000-0002-4185-055X)
- Stéphane Angers (ORCID: https://orcid.org/0000-0001-7241-9044)
- Vijay Ramaswamy (ORCID: https://orcid.org/0000-0002-6557-895X)
- Siddharth Sukumaran (ORCID: https://orcid.org/0000-0001-8382-1186)
- Paul A. Northcott (ORCID: https://orcid.org/0000-0002-1220-5252)
- Shane M. Harding (ORCID: https://orcid.org/0000-0002-5524-3566)
- Brian Gudenas (ORCID: https://orcid.org/0000-0002-9487-0300)
- Frédéric Charron (ORCID: https://orcid.org/0000-0003-3483-8672)
- Leanne Wybenga-Groot (ORCID: https://orcid.org/0000-0002-7073-9041)
- Peter B. Dirks (ORCID: https://orcid.org/0000-0001-5718-6465)
- Ahmed M. Aman (ORCID: https://orcid.org/0000-0002-0275-205X)
- Dénis Reynaud
- Carolina Nör
- Li Shen (ORCID: https://orcid.org/0000-0002-0436-0199)
- Deborah Termini
- Richard Marcellus
- Lucas Aragao
- Jonathan Magee
- Amarine Trolat
- Madeline Deane
Institutions
- Ontario Institute for Cancer Research (CA)
- St. Jude Children's Research Hospital (US)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Princess Margaret Cancer Centre (CA)
- Brain Tumour Research (GB)
- SickKids Foundation (CA)
- Montreal Clinical Research Institute (CA)
- McGill University (CA)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102202
- Citations
- 2
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 3.25