2025-08-18 トロント大学(U of T)
<関連情報>
- https://www.utoronto.ca/news/researchers-identify-new-therapeutic-approach-tackle-radiation-resistance-childhood-brain
- https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00275-7
非相同末端接合と放射線による合成致死性を標的とした、非常に高リスクなメデュロブラストーマへのアプローチ Targeting synthetic lethality between non-homologous end joining and radiation in very-high-risk medulloblastoma
Alexandria DeCarlo ∙ Graham MacLeod, ∙ Carolina Fernandes da Silva ∙ … ∙ Peter Dirks ∙ Stephane Angers ∙ Vijay Ramaswamy
Cell Reports Medicine Published:June 24, 2025
DOI:https://doi.org/10.1016/j.xcrm.2025.102202
Graphical abstract
Highlights
- Genome-wide CRISPR-Cas9 screens in bona fide SHH medulloblastoma models
- Trp53 mutations drive resistance to radiotherapy in SHH medulloblastoma
- DNA-PK identified as a radiation-specific vulnerability in TP53-mutant medulloblastoma
- DNA-PK inhibition potently sensitizes tumors to standard-of-care radiotherapy
Summary
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.
