TY  - JOUR
AU  - Vollmer, Johanna
AU  - Ecker, Jonas
AU  - Hielscher, Thomas
AU  - Valinciute, Gintvile
AU  - Ridinger, Johannes
AU  - Jamaladdin, Nora
AU  - Peterziel, Heike
AU  - van Tilburg, Cornelis Martinus
AU  - Oehme, Ina
AU  - Witt, Olaf
AU  - Milde, Till
TI  - Class I HDAC inhibition reduces DNA damage repair capacity of MYC-amplified medulloblastoma cells.
JO  - Journal of neuro-oncology
VL  - 164
IS  - 3
SN  - 0167-594X
CY  - Dordrecht [u.a.]
PB  - Springer Science + Business Media B.V
M1  - DKFZ-2023-01991
SP  - 617-632
PY  - 2023
N1  - #EA:B310#LA:B310# / 2023 Sep;164(3):617-632
AB  - MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC-driven MB to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. In this study we characterize the transcriptional effects of class I HDACi in MYC-driven MB and explore beneficial drug combinations.MYC-amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile were quantified on a microarray. Bioinformatic assessment led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested for synergy with entinostat in WST-8 metabolic activity assays in a 5 × 5 combination matrix design. Synergy was validated in cell count and flow cytometry experiments. The effect of entinostat and olaparib on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry.Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat selectively in MYC-amplified MB cells, leading to increased cell death, decreased viability and increased formation of double strand breaks, as well as increased sensitivity to additional induction of DNA damage by doxorubicin. Non-MYC-amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment.Our study identifies the combination of entinostat with olaparib as a new potential therapeutic approach for MYC-driven Group 3 MB.
KW  - DNA-damage (Other)
KW  - HDAC (Other)
KW  - MYC (Other)
KW  - Medulloblastoma (Other)
KW  - Synergy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37783879
DO  - DOI:10.1007/s11060-023-04445-w
UR  - https://inrepo02.dkfz.de/record/284402
ER  -