Abstract
<jats:p>Background: Medulloblastoma is the most common malignant pediatric brain tumor. Although advances in conventional therapies have improved survival over the years, acquired drug resistance remains a major barrier to durable cure. As dysregulation of epigenetic mechanisms is increasingly recognized as a driver of medulloblastoma pathogenesis and therapeutic adaptation, targeting epigenetic vulnerabilities represents a promising strategy to overcome treatment resistance. Methods: We generated vincristine-resistant medulloblastoma cell line models and performed chemical screening to identify therapeutically targetable vulnerabilities. Candidate hits were validated using transcriptomic analyses, chromatin immunoprecipitation, and CRISPR-mediated genetic ablation to define the molecular mechanisms underlying drug sensitivity. Results: Chemical screening identified multiple active epigenetic compound classes capable of resensitizing vincristine-resistant medulloblastoma cells, including histone methyltransferase inhibitors, histone deacetylase inhibitors, and bromodomain inhibitors. Among these, the CBP/p300 bromodomain inhibitor SGC-CBP30 emerged as the most potent sensitizer to vincristine. Transcriptomic profiling revealed that, while ABCB1 was among the most highly upregulated genes in resistant cells, SGC-CBP30 treatment selectively downregulated ABCC3 and ABCA4, an effect not observed in parental cells. Mechanistically, chromatin immunoprecipitation demonstrated enrichment of p300 and H3K27ac at the ABCC3 and ABCA4 promoters in resistant cells, which was markedly reduced following SGC-CBP30 treatment. Consistent with these findings, genetic ablation of CREBBP or EP300 phenocopied the effects of pharmacological inhibition. Analysis of patient datasets further demonstrated elevated CREBBP, EP300, and ABCC3 expression in SHH MB, with positive correlations between ABCC3 and both CREBBP and EP300, supporting the clinical relevance of this regulatory axis. Conclusions: Together, our findings demonstrate that CBP/p300 activity contributes to acquired vincristine-resistance in medulloblastoma. Targeting this axis represents a promising strategy to overcome drug resistance and enhance the efficacy of vincristine-based chemotherapy particularly in the context of relapsed or refractory disease.</jats:p>