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 8

Allosteric IDH1 inhibitor ivosidenib synergies with GEM against iCCA with wtIDH1 in preclinical models.

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Allosteric IDH1 inhibitor ivosidenib synergies with GEM against iCCA wit...
(A) Box plot illustrating the relative viability of iCCA organoids after treatment of ivosidenib and GEM for 72 hours (n = 5). Scale bar: 100 μm. (B) Tumor growth curves of iCCA PDX xenografts from 3 chemotherapy-naive patients with iCCA. Representative tiles of IDH1 IHC staining are shown below. Scale bar: 100 μm. (C) Kaplan-Meier tumor volume-free (500 mm3) analysis of iCCA PDX xenografts. (D) Gross view of the iCCA PDX xenografts after treatment of ivosidenib and/or GEM. (E) Box plot showing the tumor volume of iCCA PDX xenografts. (F) Spectrophotometry detecting the free magnesium levels in serum, liver, normal bile duct, and xenografts collected from the iCCA PDX models. (G) Molecular mechanisms and therapeutic vulnerability of IDH1 in iCCA’s chemoresistance to GEM. In iCCA cells, overexpressed IDH1 oxidizes isocitrate to generate αKG and NADPH, thereby reducing the oxidative stress induced by GEM, maintaining redox homeostasis, and ultimately leading to their chemoresistance to GEM. If IDH1 inhibitors (such as ivosidenib or GSK321) are used in combination with GEM, they can inhibit the catalytic function of IDH1, reducing the production of NADPH and GSH involved in antioxidant stress responses. This leads to intracellular redox imbalance, consequently reversing the chemoresistance of iCCA to GEM and resulting in tumor proliferation arrest and cell death. The image was created with BioRender. Statistical analysis was performed with (A and E) 1-way ANOVA, (C) log-rank test, and (F) 2-sided t test. Data represent mean ± SEM. See also Supplemental Figures 11 and 12.