Targeting CBP/p300 Overcomes Acquired Vincristine Resistance in Medulloblastoma

ABSTRACT 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. PLAIN ENGLISH SUMMARY Medulloblastoma is the most common cancerous brain tumor in children. Although many children respond well to the treatment, some tumors become resistant to chemotherapy, making them much harder to treat. Understanding why this resistance develops could lead to better treatment options for children whose cancer returns or no longer respond to therapy. In this study, we created laboratory models of medulloblastoma that had become resistant to the chemotherapy drug vincristine. We then tested a collection of drugs to identify compounds, which would restore the cancer cells’ sensitivity to treatment. We have discovered that several drugs were effective, with one compound, called SGC-CBP30, showing particularly strong activity. We investigated how SGC-CBP30 works and found that it decreases the activity of genes that are linked to chemotherapy resistance. Using multiple complementary experimental approaches, we confirmed that this gene-regulating pathway plays an important role in helping medulloblastoma cells survive treatment. Our findings suggest that targeting this pathway could restore the effectiveness of chemotherapy in drug-resistant tumors. Although further research is needed before this approach can be used in patients, these results provide a promising foundation for developing new treatments for children with relapsed or treatment-resistant medulloblastoma.