Disruption of DNA Repair and Survival Pathways through Heat Shock Protein Inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation Therapy.

ABSTRACT:

Purpose

Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemoradiation in glioma stem cells (GSC). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemoradiation in vitro and in vivo.

Experimental design

The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize glioblastoma (GBM) to chemoradiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic

SUBMITTER: Xu J 

PROVIDER: S-EPMC9064967 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature