Faculty, Staff and Student Publications
Publication Date
8-1-2024
Journal
Advanced Science
Abstract
PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient-derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy.
Keywords
Glioblastoma, Animals, Humans, Poly(ADP-ribose) Polymerase Inhibitors, Mice, Zebrafish, Mice, Nude, Cell Line, Tumor, Disease Models, Animal, Brain Neoplasms, BET, cell cycle, DNA damage, glioblastoma, PARP
DOI
10.1002/advs.202307747
PMID
38896791
PMCID
PMC11321613
PubMedCentral® Posted Date
6-19-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Oncology Commons, Public Health Commons
