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Zeuner, Simon; Vollmer, Johanna; Sigaud, Romain; Oppermann, Sina; Peterziel, Heike; ElHarouni, Dina; Oehme, Ina; Witt, Olaf; Milde, Till; Ecker, Jonas

Combination drug screen identifies synergistic drug interaction of BCL-XL and class I histone deacetylase inhibitors in MYC-amplified medulloblastoma cells

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  • Medientyp: E-Artikel
  • Titel: Combination drug screen identifies synergistic drug interaction of BCL-XL and class I histone deacetylase inhibitors in MYC-amplified medulloblastoma cells
  • Beteiligte: Zeuner, Simon; Vollmer, Johanna; Sigaud, Romain; Oppermann, Sina; Peterziel, Heike; ElHarouni, Dina; Oehme, Ina; Witt, Olaf; Milde, Till; Ecker, Jonas
  • Erschienen: Springer Science and Business Media LLC, 2024
  • Erschienen in: Journal of Neuro-Oncology
  • Sprache: Englisch
  • DOI: 10.1007/s11060-023-04526-w
  • ISSN: 0167-594X; 1573-7373
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Purpose</jats:title> <jats:p>Patients with <jats:italic>MYC</jats:italic>-amplified Group 3 medulloblastoma (MB) (subtype II) show poor progression-free survival rates. Class I histone deacetylase inhibitors (HDACi) are highly effective for the treatment of <jats:italic>MYC</jats:italic>-amplified MB in vitro and in vivo. Drug combination regimens including class I HDACi may represent an urgently needed novel treatment approach for this high risk disease.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>A medium-throughput in vitro combination drug screen was performed in three <jats:italic>MYC</jats:italic>-amplified and one non-<jats:italic>MYC</jats:italic>-amplified MB cell line testing 75 clinically relevant drugs alone and in combination with entinostat. The drug sensitivity score (DSS) was calculated based on metabolic inhibition quantified by CellTiter-Glo. The six top synergistic combination hits were evaluated in a 5 × 5 combination matrix and a seven-ray design. Synergy was validated and characterized by cell counts, caspase-3-like-activity and poly-(ADP-ribose)-polymerase-(PARP)-cleavage. On-target activity of drugs was validated by immunoprecipitation and western blot. BCL-XL dependency of the observed effect was explored with siRNA mediated knockdown of <jats:italic>BCL2L1</jats:italic>, and selective inhibition with targeted compounds (A-1331852, A-1155463).</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>20/75 drugs effectively reduced metabolic activity in combination with entinostat in all three <jats:italic>MYC</jats:italic>-amplified cell lines (DSS ≥ 10). The combination entinostat and navitoclax showed the strongest synergistic interaction across all <jats:italic>MYC</jats:italic>-amplified cell lines. siRNA mediated knockdown of <jats:italic>BCL2L1</jats:italic>, as well as targeted inhibition with selective inhibitors showed BCL-XL dependency of the observed effect. Increased cell death was associated with increased caspase-3-like-activity.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Our study identifies the combination of class I HDACi and BCL-XL inhibitors as a potential new approach for the treatment of <jats:italic>MYC</jats:italic>-amplified MB cells.</jats:p> </jats:sec><jats:sec> <jats:title>Graphical abstract</jats:title> </jats:sec>