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

• Verfasst von: Zeuner, Simon [VerfasserIn]
• Verfasst von: Vollmer, Johanna [VerfasserIn]
• Verfasst von: Sigaud, Romain [VerfasserIn]
• Verfasst von: Oppermann, Sina [VerfasserIn]
• Verfasst von: Peterziel, Heike [VerfasserIn]
• Verfasst von: ElHarouni, Dina [VerfasserIn]
• Verfasst von: Oehme, Ina [VerfasserIn]
• Verfasst von: Witt, Olaf [VerfasserIn]
• Verfasst von: Milde, Till [VerfasserIn]
• Verfasst von: Ecker, Jonas [VerfasserIn]
• Titel: Combination drug screen identifies synergistic drug interaction of BCL-XL and class I histone deacetylase inhibitors in MYC-amplified medulloblastoma cells
• Verf.angabe: Simon Zeuner, Johanna Vollmer, Romain Sigaud, Sina Oppermann, Heike Peterziel, Dina ElHarouni, Ina Oehme, Olaf Witt, Till Milde, Jonas Ecker
• E-Jahr: 2024
• Jahr: 07 January 2024
• Umfang: 14 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 26.03.2024
• Titel Quelle: Enthalten in: Journal of neuro-oncology
• Ort Quelle: Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983
• Jahr Quelle: 2024
• Band/Heft Quelle: 166(2024), Seite 99-112
• ISSN Quelle: 1573-7373
• DOI: doi:10.1007/s11060-023-04526-w
• Datenträger: Online-Ressource
• Sprache: eng
• Bibliogr. Hinweis: Errata: Kocheise, Lorenz, 1994 - : Corrigendum: PD-1/PD-L1 immune checkpoint therapy demonstrates favorable safety profile in patients with autoimmune and cholestatic liver disease
• Sach-SW: BCL-XL
• Sach-SW: Drug screen
• Sach-SW: HDAC
• Sach-SW: Medulloblastoma
• Sach-SW: MYC
• K10plus-PPN: 1884376304

Abstract

Purpose: Patients with MYC-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 MYC-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. Methods: A medium-throughput in vitro combination drug screen was performed in three MYC-amplified and one non-MYC-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 BCL2L1, and selective inhibition with targeted compounds (A-1331852, A-1155463). Results: 20/75 drugs effectively reduced metabolic activity in combination with entinostat in all three MYC-amplified cell lines (DSS ≥ 10). The combination entinostat and navitoclax showed the strongest synergistic interaction across all MYC-amplified cell lines. siRNA mediated knockdown of BCL2L1, 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. Conclusion: Our study identifies the combination of class I HDACi and BCL-XL inhibitors as a potential new approach for the treatment of MYC-amplified MB cells.