EZH2 inhibition sensitizes MYC-high medulloblastoma cancers to PARP inhibition by regulating NUPR1-mediated DNA repair.

MYC-driven medulloblastomas (MB) are highly aggressive pediatric brain tumors with poor outcomes, and effective therapies remain limited despite intensive multimodal treatments. Targeting MYC directly is challenging, but exploiting MYC-mediated synthetic lethality holds promise. In this study, we investigated the combined effects of EZH2 and PARP inhibitors in MYC-high medulloblastoma and demonstrated that EZH2 inhibition significantly increased the sensitivity of MYC-high MB tumor cells to PARP inhibitors. This effect occurs through the upregulation of NUPR1, which promotes error-prone non-homologous end-joining (NHEJ) DNA repair by facilitating the recruitment of the XRCC4-LIG4 complex to DNA damage sites. This amplification of error-prone NHEJ DNA repair leads to genetic instability and eventual cell death in cells treated with the PARP inhibitor. The synergistic effect of EZH2 and PARP inhibitors was further validated in both in vitro and in vivo MB models without observed toxicity. These findings reveal a novel therapeutic strategy for MYC-high MB by co-targeting EZH2 and PARP, suggesting that this combination could potentially overcome the clinical challenges associated with this aggressive tumor subtype and warrants further investigation in clinical trials.