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

DeCarlo, A.; Macleod, G.; Fernandes da Silva, C.; Shen, L.; Aragao, L.; Sie, M.; Termini, D.; Magee, J.; Gudenas, B.; Sukumaran, S.; Charron, F.; Marcellus, R.; Al-Awar, R.; Aman, A.; Tabori, U.; Nor, C.; Northcott, P.; Dirks, P. B.; Angers, S.; Ramaswamy, V.

doi:10.1101/2024.11.11.622104

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bioRxiv · 10.1101/2024.11.11.622104

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

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Abstract

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

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DeCarlo, A., Macleod, G., Fernandes da Silva, C., Shen, L., Aragao, L., Sie, M., Termini, D., Magee, J., Gudenas, B., Sukumaran, S., Charron, F., Marcellus, R., Al-Awar, R., Aman, A., Tabori, U., Nor, C., Northcott, P., Dirks, P. B., Angers, S., Ramaswamy, V.. 2024-11-12. Targeting synthetic lethality between non-homologous end joining and radiation in very high-risk SHH medulloblastoma. https://doi.org/10.1101/2024.11.11.622104

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