The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1
Xiuxian Li, Zhixiao Song, Shusheng Lin, Man Luo, Shaoru Liu, Yang Liu, Fapeng Zhang, Leibo Xu, Chao Liu, Honghua Zhang
Xiuxian Li, Zhixiao Song, Shusheng Lin, Man Luo, Shaoru Liu, Yang Liu, Fapeng Zhang, Leibo Xu, Chao Liu, Honghua Zhang
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Research Article Hepatology Metabolism Oncology

The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1

Abstract

Gemcitabine-based chemotherapy is the standard treatment regimen for advanced intrahepatic cholangiocarcinoma (iCCA), but the frequent presence of chemoresistance limits its efficacy. Here, we identified isocitrate dehydrogenase 1 (IDH1) as the crucial target that confers chemoresistance of iCCA to gemcitabine using a druggable CRISPR/Cas9 library. The positive association between IDH1 expression and chemoresistance was revealed in a gemcitabine-treated iCCA cohort and with cell-based drug sensitivity assays. Utilizing patient-derived organoids, cell line–derived xenografts, and patient-derived xenografts, we demonstrated that IDH1 knockdown or IDH1 pharmacological inhibition facilitated gemcitabine efficacy in these preclinical iCCA models carrying wild-type IDH1 (wtIDH1). Mechanistically, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate and NNADPH, thereby creating a mechanism to manage the oxidative stress induced by gemcitabine, maintaining cellular redox homeostasis, and, ultimately, leading to chemoresistance to gemcitabine. Significantly, ivosidenib, the FDA-approved allosteric IDH1 inhibitor, demonstrated synergistic antitumor efficacy with gemcitabine in wtIDH1 preclinical iCCA models through boosting intracellular oxidative stress under physiological conditions. The low level of Mg2+, an ion that competitively hinders binding of ivosidenib on wtIDH1, in the iCCA tumor microenvironment contributed to the expanded therapeutic window for use of ivosidenib in patients with iCCA. Our work revealed the potency of combining targeting IDH1 and chemotherapy against wtIDH1 iCCA and other tumors.

Authors

Xiuxian Li, Zhixiao Song, Shusheng Lin, Man Luo, Shaoru Liu, Yang Liu, Fapeng Zhang, Leibo Xu, Chao Liu, Honghua Zhang

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Figure 1

Higher IDH1 was associated with the resistance of iCCA to GEM-based chemotherapy.

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Higher IDH1 was associated with the resistance of iCCA to GEM-based chem...
(A) Luminescence denoted relative cellular viability of iCCA cells treated with serial concentrations of GEM for 72 hours (n = 3 replicates), and the calculated IC50 are shown in brackets. (B) Colony-formation assay of iCCA cells treated with serial concentrations of GEM for 10 days. (C) Workflow of the synthetic lethal screen in GEM-resistant HuCCT1 cells with druggable CRISPR/Cas9 library screening (n = 3 replicates). (D) Dot plot showing the synthetic lethality of each gene in promoting HuCCT1 resistance to 14-day GEM treatment (1 μM), where IDH1 was identified as the top synthetic lethal hit. (E) Spearman’s correlation analysis of the IDH1 expression level, with IC50 in response to GEM in iCCA cells. (F) Tumor organoids derived from patients with iCCA were treated with GEM for 72 hours to evaluate their relative viability (n = 9). These organoids were dichotomized by the IDH1 expression level of their corresponding primary tumor sections. Scale bar: 100 μm. (G) Kaplan-Meier OS analysis of patients with iCCA who received radical resection and adjuvant GEM-based chemotherapy in the SYSMH cohort (n = 174). Representative tiles of IDH1 IHC staining are shown below, and samples with IHC score >1.3 were classified as “IDH1 high.” Scale bar: 100 μm. Statistical analysis was performed with (E) Spearman’s correlation coefficient, (F) 1-way ANOVA, and (G) log-rank test. Data represent mean ± SEM. See also Supplemental Figure 1.