Investigating the role of GSK3β inhibition by Elraglusib in pediatric acute myeloid leukemia

Glycogen synthase kinase-3 (GSK3) has emerged as a critical regulator of multiple cellular processes and a potential therapeutic target in various cancers, including AML. The role of GSK3 isoforms (α and β) in AML remains controversial. Gene expression analysis of a pediatric AML cohort revealed elevated GSK3 levels compared to healthy donors and distinct gene expression patterns in response to GSK inhibitors, particularly in AMKL, suggesting heightened sensitivity to GSK3 inhibition. Functional studies demonstrated that individual GSK3A/B depletion caused significant reduction in murine megakaryoblastic leukemia models but showed variable effects in human leukemia cell lines, although all models were uniformly sensitive to the GSK3B inhibitor Elraglusib. Interestingly, we observed that Elraglusib exerts GSK3B-independent effects, acting as a classical chemotherapeutic agent. Combining Elraglusib with the mitotic agent Palbociclib reversed these effects. These findings provide valuable insights into the mechanism of action and off-target effects of Elraglusib, with important implications for ongoing clinical trials and future development of GSK3-targeted therapies.

Publication History

Article published online:
09 May 2025