Mutant Isocitrate Dehydrogenase 1 Sensitizes Intrahepatic Cholangiocarcinoma Cells to MDM2 Inhibitors.

Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 10% to 25% of intrahepatic cholangiocarcinoma (iCCA) cases. Despite significantly prolonged progression-free survival, the mutant IDH1 (mIDH1) inhibitor ivosidenib achieved only a 3% response rate in clinical trials, highlighting the need for new therapeutic options for IDH1 mutation (IDH1mut) iCCA. Our in silico analysis demonstrated that IDH1mut and TP53 mutation (TP53mut) were mutually exclusive in iCCA cells and that IDH1mut iCCA cells expressed higher mouse double minute 2 homolog (MDM2) levels than IDH1wt iCCA cells. Chromatin immunoprecipitation quantitative polymerase chain reaction assay showed enrichment of histone-3-lysine-4 tri-methylation (H3K4me3), an indicator of active gene transcription, at the MDM2 promoter in IDH1mut iCCA cells, confirming the data from ENCODE histone-seq. Treatment with a mIDH1 inhibitor reduced 2-hydroxyglutarate (2-HG) levels, enhanced lysine-specific demethylase 5 (KDM5) activity, and attenuated the H3K4me3/H3K4me1 ratio at the MDM2 promoter, which was accompanied by a reduction in MDM2 expression and an increase in wild-type TP53 (wtTP53) protein levels in IDH1mut iCCA cells. The effect of the mIDH1 inhibitor on MDM2 mRNA levels was reversed by treatment with KDOAM-25 citrate, a pan-KDM5 inhibitor. In addition, MDM2 inhibitors that could block MDM2-mediated wtTP53 degradation selectively induced TP53 reactivation, cell-cycle arrest, and growth inhibition in IDH1mut iCCA cells. The combination of mIDH1 and MDM2 inhibitors synergistically suppressed the proliferation of IDH1mut iCCA cells. Our study delineated a novel mIDH1-MDM2-wtTP53 axis and its potential application for wtTP53 reactivation therapy in IDH1mut iCCA. SIGNIFICANCE: IDH1 mutation enhances MDM2 expression by inhibiting KDM5 activity to promote the proliferation of TP53wt iCCA cells. Cotargeting MDM2 and mIDH1 yields a synergistic effect on growth inhibition, providing a new strategy for treating patients with iCCA with IDH1 mutations.