Medulloblastoma is the most common malignant pediatric brain tumor. Although survival has improved with conventional therapies, acquired resistance to chemotherapeutic agents remains a major barrier to durable cure. Increasing evidence implicates epigenetic dysregulation in medulloblastoma pathogenesis and adaptive resistance, suggesting epigenetic regulators could be exploitable therapeutic vulnerabilities. This study therefore tested whether targeting epigenetic mechanisms can overcome acquired resistance to the microtubule inhibitor vincristine in medulloblastoma models.
The authors generated vincristine-resistant medulloblastoma cell line models to mimic acquired chemotherapy resistance. They performed a chemical screen focusing on epigenetic modulators to identify compounds that re-sensitize resistant cells to vincristine. Candidate hits from the screen were validated using transcriptomic profiling, chromatin immunoprecipitation (ChIP) assays to interrogate chromatin marks and cofactor occupancy, and CRISPR-mediated genetic ablation to test dependence on specific epigenetic regulators.
Screening revealed several classes of epigenetic inhibitors capable of resensitizing vincristine-resistant medulloblastoma cells. Active classes included histone methyltransferase inhibitors, histone deacetylase inhibitors, and bromodomain inhibitors. These findings indicate multiple epigenetic pathways can modulate chemosensitivity in the resistant state.
Among bromodomain-targeting compounds, the CBP/p300 bromodomain inhibitor SGC-CBP30 emerged as the most potent sensitizer to vincristine in the resistant cell models. This pharmacologic result motivated additional mechanistic studies to define how CBP/p300 inhibition restores vincristine sensitivity.
Transcriptomic profiling of vincristine-resistant cells identified upregulation of multiple genes, with ABC transporter family members among the most highly induced. Notably, ABCB1 was reported as one of the highly upregulated genes in resistant cells. Treatment with SGC-CBP30 produced selective transcriptional changes in resistant cells: ABCC3 and ABCA4 were downregulated after SGC-CBP30 exposure, an effect not observed in parental (non-resistant) cells. These selective transcriptional responses suggest SGC-CBP30 targets resistance-associated transcriptional programs rather than broadly suppressing ABC transporters in all cells.
To probe the chromatin basis for altered transporter expression, the authors performed chromatin immunoprecipitation. ChIP experiments demonstrated enrichment of p300 and the active histone mark H3K27ac at the promoters of ABCC3 and ABCA4 in resistant cells. Following SGC-CBP30 treatment, this promoter enrichment of p300 and H3K27ac was markedly reduced. These data support a model in which CBP/p300 maintains acetylation and transcriptional activation of specific ABC transporter genes in the resistant state, and bromodomain inhibition disrupts that activation.
Genetic experiments using CRISPR-mediated ablation of CREBBP (encoding CBP) or EP300 phenocopied the effects of pharmacologic CBP/p300 inhibition. Loss of CREBBP or EP300 reproduced the transcriptional and sensitizing effects observed with SGC-CBP30, providing orthogonal evidence that CBP/p300 activity is required for the resistant phenotype targeted by the compound.
To assess clinical relevance, the authors evaluated patient gene expression datasets. They report elevated expression of CREBBP, EP300, and ABCC3 in the SHH subgroup of medulloblastoma. Positive correlations were observed between ABCC3 expression and both CREBBP and EP300. These associations link the CBP/p300–ABCC3 regulatory axis to a defined clinical subgroup, supporting translational relevance of targeting CBP/p300 in at least a subset of medulloblastoma patients.
Collectively, the findings demonstrate that CBP/p300 activity contributes to acquired vincristine resistance in medulloblastoma models. Pharmacologic inhibition of the CBP/p300 bromodomain with SGC-CBP30, as well as genetic ablation of CREBBP or EP300, reverses resistance-associated transcriptional programs and re-sensitizes cells to vincristine. The study supports the concept that targeting epigenetic coactivators can overcome chemotherapy resistance and suggests CBP/p300 inhibition is a promising strategy to enhance vincristine efficacy, particularly for relapsed or refractory medulloblastoma.
This report is a preprint and has not been peer reviewed. The abstract and available summary do not provide specific experimental parameters in the text reviewed here, such as the exact cell lines used, quantitative effect sizes, dosing regimens, time courses, in vivo efficacy or toxicity data, or detailed safety assessments for CBP/p300 inhibition. Those details are not reported in the abstract and should be consulted in the full preprint and supplementary material for complete methods and data. Additionally, clinical translation will require evaluation of pharmacokinetics, therapeutic window, and safety in appropriate preclinical models and ultimately clinical trials.