Gemcitabine-based chemotherapy is the standard treatment regime 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 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 pre-clinical iCCA models carrying wild-type IDH1 (wtIDH1). Mechanistically, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate and NADPH, thereby coping with the oxidative stress induced by gemcitabine, maintaining cellular redox homeostasis, and ultimately leading to their chemoresistance to gemcitabine. Significantly, ivosidenib, the FDA-approved allosteric IDH1 inhibitor, demonstrated synergistic anti-tumor efficacy with gemcitabine in wtIDH1 pre-clinical 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 iCCA tumor microenvironment contributed to the expanded therapeutic window of ivosidenib in patients with iCCA. Our work revealed the potency of combining targeting IDH1 and chemotherapy against wtIDH1 iCCA and other tumors.
Keywords: Cancer gene therapy; Hepatology; Liver cancer; Metabolism; Oncology.