Targeting cholesterol homeostasis eliminates drug-tolerant persister cells in glioblastoma

ABSTRACT: The transition of cancer cells between drug-sensitive and drug-tolerant persister phenotypes drives treatment failures. Using glioblastoma models, we identified MRK-740, an inhibitor of H3K4 methyltransferase PRDM7/9, as a potent enhancer of chemotherapy-induced cell death, resulting in elimination of glioblastoma persister cells. Mechanistic investigations as well as analysis of glioblastoma specimens revealed that H3K4me3 is a transcription-activating mark at the promoters of key genes involved in cholesterol biosynthesis. The inhibition of H3K4 methylation in cells treated with microtubule-targeting agents led to the disruption of cholesterol homeostasis and LXR-dependent cholesterol efflux, ultimately depleting intracellular cholesterol and causing the death of persisters. Furthermore, we have developed a brain permeable microtubule-targeting agent to validate these mechanistic findings in vivo. We show that a combination of our novel chemotherapeutic agent and a brain permeable LXR agonist significantly extends survival in a glioblastoma mouse model. These results uncover the importance of balanced cholesterol homeostasis in chemotherapy tolerance.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Cancer

SUBMITTER: Jason Low  

LAB HEAD: Lenka Munoz

PROVIDER: PXD050643 | Pride | 2025-12-22

REPOSITORIES: Pride