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BET bromodomain Inhibition Potentiates Radiosensitivity by Reprograming DNA Damage Repair in H3K27M-Mutant Glioma

ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is one of the devastating childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only1%. Several clinical trials have attempted to enhance radiation anti-tumor activity using radiosensitizing agents, though none have been successful in doing so. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DIPG. Using high-throughput radiosensitivity screening, we identified bromo- and extra-terminal domain (BET) protein inhibitors as potent radiosensitizers in DIPG. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DIPG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA- and CUT-RUN-sequencing showed that BET bromodomain inhibitors regulate the expression of DNA repair genes mediated by H3K27acetylation at enhancers. BET bromodomain inhibitors enhanced DIPG radiation-response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitor as a novel radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment DIPG.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236598 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 ÂµM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).

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BET bromodomain Inhibition Potentiates Radiosensitivity by Reprograming DNA Damage Repair in H3K27M-Mutant Glioma

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