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Mutant IDH1 activates JOSD2-YAP/TAZ in a non-classical manner to sustain intrahepatic cholangiocarcinoma cell growth

ABSTRACT: Gain of function mutations in isocitrate dehydrogenase 1 are one of the most common genetic lesions in intrahepatic cholangiocarcinoma (ICC). The mutant IDH1 (mIDH1) causes aberrant metabolic, epigenetic and differentiation process by converting α-ketoglutarate (α-KG) to onco-metabolite 2-hydroxyglutarate (2-HG). However, mIDH1 inhibitor ivosidenib appears much more effective in acute myeloid leukemia than that in ICC, suggesting that in addition to these common mechanisms, other pathways may be also involved. Our results indicated that mIDH1 exhibited high correlation of transcription profiles with JOSD2, a deubiquitinating enzyme reported to stabilize YAP/TAZ by our previous work. Further exploration suggested that mIDH1 up-regulated JOSD2 protein stability independent of 2-HG and couldn’t be intervened by ivosidenib. The targeted silence of JOSD2 exhibited more potent anti-tumor effect in cells with mIDH1 than wild type cells. Together, this study may provide novel insights for understanding the tumor-promoting effects of mIDH1 to derive new therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231839 | GEO | 2025/04/30

REPOSITORIES: GEO

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Project description:A phase-1, multi-center study in recurrent non-enhancing gliomas with IDH1 R132H mutation for patients who require surgery. The purpose of this study is to evaluate the suppression of 2-HG (2-hydroxyglutarate) by comparing the concentration of 2-HG in resected tumors from IDH1 mutant glioma subjects following AG-120 or AG-881 treatment with the 2-HG concentration in untreated, control tumors. The safety, tolerability, PK/PD, and anti tumor activity data from the study in subjects with recurrent non-enhancing Grade 2/3 LGG with an IDH1 R132H mutation for whom surgical resection is indicated will identify the recommended dose of AG-120 and AG-881 for future studies in glioma. Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDHglioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration ofD-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDHLGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

Project description:As genomic analysis technology has advanced, it has become possible to sub-classify intrahepatic cholangiocarcinoma (ICC) at the histological or molecular level. However, there are no truly representative models of ICC subtypes for use in studying developmental differences, carcinogenesis, and personalized drug response. Here, we sought to verify recent suggested two subgroup of ICC in organoids model, compare the characteristics between LD and SD type of ICC, and find the type-specific gene expression profile and targetable pathway as a therapeutic target. ICC organoids from 16 patients pathologically diagnosed with cholangiocarcinoma were prepared according to a previously established organoid culture protocol. ICC patients were subclassified into small-duct (SD) type and large-duct (LD) type according to histological characteristics and S100P, N-cadherin, and CD56 expression. ICC organoids were successfully established within one month and exhibited a morphology similar to that of their matching primary cancer. LD- and SD-type organoids exhibited histologic phenotypes and staining patterns characteristic of the corresponding ICC subtypes. ICC organoids showed high concordance of somatic mutations with primary tumors. Unsupervised principal component analysis clustering effectively separated each type of ICC. Differential gene expression revealed significant enrichment on KRAS, TGFβ and ERBB2 signaling pathways in LD-type compared with SD-type ICC (P<0.05). Gene set enrichment analysis further demonstrated that the cholangiocarcinoma class 2 signature, defined by Andersen et al., was significantly enriched in the LD-type (enrichment score=2.19, P<0.001). A protein-protein interaction network analysis identified ZNF217 as a significant hub protein (odds ratio=4.96, P=0.0105). We successfully performed prospective modeling of histological subtype specification using patient-derived ICC organoids. Moreover, gene expression profiling of ICC organoids enabled identification of type-specific targetable pathways.

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Mutant IDH1 activates JOSD2-YAP/TAZ in a non-classical manner to sustain intrahepatic cholangiocarcinoma cell growth

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