Effect of the IDH1 inhibitor combined with hypomethylating agents on acute myeloid leukemia.

OBJECTIVE: Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in approximately 6-10% of acute myeloid leukemia (AML) patients. Ivosidenib (IVO) is a small-molecule inhibitor of mutant IDH1. This study delves into the mechanism of IVO with hypomethylating agents (HMAs) (azacitidine or decitabine) for treating IDH1-mutated AML through the PI3K/AKT pathway.

METHODS: IDH1R132H-mutated MOLM-13 (IDH1R132H-MOLM-13) cells were constructed. The effects of the drugs, both individually and in combination, on IDH1R132H-MOLM-13 cell proliferation and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry, with combination index (CI) values calculated using CompuSyn software. IDH1, DNMT1, PI3K and AKT gene mRNA levels, and the PI3K/AKT pathway- and histone lysine methylation-related protein levels in IDH1R132H-MOLM-13 cells were determined by RT-qPCR and Western blot.

RESULTS: IDH1R132H-mutated MOLM-13 cells (IDH1R132H-MOLM-13) were successfully constructed. The IDH1 inhibitor, either as a monotherapy or combined with HMAs, effectively inhibited IDH1R132H-MOLM-13 cell proliferation, and the combination therapy exhibited synergistic effects (CI < 1). The combination therapy increased cell proportion in the G2/M phase and apoptotic rate. Both treatment modalities reduced IDH1, DNMT1, PI3K and AKT mRNA levels and histone lysine methylation levels (H3K4me3, H3K9me3, H3K27me3); besides, PI3K and AKT phosphorylation levels were reduced, with the reductions being more significant in cells undergoing combination therapy. The indexes did not differ significantly between cells undergoing the two modalities of combined treatments.

CONCLUSION: The IDH1 inhibitor with HMAs suppressed IDH1R132H-MOLM-13 cell proliferation and viability and decreased the methylation level by repressing the phosphorylation of the PI3K/AKT pathway, showing a synergistic inhibitory effect.