In this study, MDM2 and p53 were identified as potential drug targets in ST-EPN-RELA ependymoma in vitro, with low-dose Actinomycin-D being capable of reactivating p53 function and thereby re-establishing its tumour-suppressive role, whereas Nutlin-3 mediated similar effects yet only in the ependymoma cell line representing a supratentorial RELA-positive ependymoma subtype harbouring an additional homozygous CDKN2A deletion. Here, RELA is linked to ependymoma.