Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells

Abstract

In glioblastoma, several histone demethylase genes (KDMs) are overexpressed compared to normal brain tissue. The development of resistance to Temozolomide (TMZ) is associated with a temporary increase in the expression of KDM5A and other KDMs, a phenomenon we term “epigenetic resilience.” We hypothesized that targeting KDMs could eliminate cells that survive cytotoxic therapy.

We investigated the effects of two KDM inhibitors, JIB 04 and CPI-455, on glioblastoma cells and discovered that both inhibitors are more effective against TMZ-resistant cells than against native ones. Due to its lower IC50, we focused on JIB 04, which targets KDM5A and other KDMs. Our research demonstrated that JIB 04 activates autophagic and apoptotic pathways, disrupts cell cycle progression, inhibits cell clonogenicity, and dephosphorylates Akt, thereby deactivating a key pro-survival pathway.

In vitro combination treatments of temozolomide and JIB 04 showed that these drugs can have a strong synergistic effect under certain conditions, suggesting that JIB 04 may target cells that evade the G2 block induced by TMZ. We also assessed JIB 04′s ability to cross the blood-brain barrier and found that it reaches bioactive concentrations in the brain. Additionally, a pilot in vivo study in an orthotopic GB xenograft model indicated a trend toward increased survival in treated mice, with a Hazard Ratio of 0.5.

In summary, we propose that combining cytotoxic drugs with agents targeting the epigenetic landscape could provide new therapeutic strategies for treating this invariably fatal CPI-455 disease.