In:
Journal of Neuro-Oncology, Springer Science and Business Media LLC, Vol. 166, No. 1 ( 2024-01), p. 99-112
Abstract:
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. Graphical abstract
Type of Medium:
Online Resource
ISSN:
0167-594X
,
1573-7373
DOI:
10.1007/s11060-023-04526-w
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2024
detail.hit.zdb_id:
2007293-4
