Joshua Nahm

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignant liver cancer, specifically of the second order bile ducts.¹ With a five-year survival of 9% and a greater than 140% increase in incidence over the past 40 years, ICC is a pressing global issue.¹ Diagnosis is complex, involving a combination of history, imaging, laboratory values, and biopsy.^1,2 Due to the frequently unresectable nature of ICC tumors, genome sequencing of commonly mutated biomarkers such as IDH1/2, FGFR2, KRAS, and TP53 has been increasingly utilized.^1,2 Current treatment options include surgery with margin-negative resection, advanced external beam radiation, combination chemotherapies, and targeted therapies against genetic abnormalities.^1–4 One such abnormality includes IDH1/2 mutant (mIDH) ICC. This variant causes the accumulation of an oncometabolite, R-2-hydroxyglutarate (2-HG), which competitively targets histone demethylases, ten-eleven translocation (TET) DNA demethylases, and other metabolic enzymes normally mediated by wild-type IDH.^2,3

Objective: In this narrative review, we explored the viability and development of various targeted therapies against mIDH ICC.

Search Methods: An online search in the PubMed database was conducted from 2017-2025 using the following keywords: “intrahepatic cholangiocarcinoma,” “IDH,” “non-fluke,” “targeted therapies,” “2-hydroxyglutarate.”

Results: The fundamental challenge of treating mIDH ICC is its intratumor heterogeneity. A study compared mIDH (IDH-sg) and non-mIDH subgroups (IDH-NO) and determined that the IDH-sg demonstrated greater hypermethylation with less T cell infiltration and cytotoxicity. This reflected a distinctly colder tumor microenvironment that is presumed to contribute to mIDH ICC’s resistance to standard therapies.^5,6 Targeted inhibitors such as AG-120 (ivosidenib) have demonstrated the ability to restore TET2 function and improve CD8+ T cell activity. AG-120 induces type I interferon signaling, which contributes to the production of an innate immune response. Additionally, it suppresses chemokines shown to downregulate T cell recruitment, such as CXCL1, CXCL2, and CCL2.⁶ Dasatinib, an SRC kinase inhibitor, promotes the formation of the MAGi1-PP2A complex. This complex dephosphorylates downstream targets such as pS6, which inactivates cell signaling downstream of 2-HG. Western blot analysis of common tumor markers indicated that dasatinib was highly specific to this pathway and did not interact with other commonly mutated pathways such as mTOR.⁷ JQ1, a BET inhibitor, induces apoptosis in mIDH ICC through mechanisms distinct from MYC downregulation and suppresses the G1/S transition.⁸ Upregulation of BIM and BAX, proapoptotic genes, was noted. In a Phase II trial, olaparib, a PARP inhibitor, did not reach its primary endpoint of an objective response. However, eight patients were found to have a clinical benefit, with greater than six months of progression-free survival. Notably, it was found that these patients had statistically significant lower median baseline levels of 2-HG, as well as increases in median percent change of total 2-HG.⁹

Conclusions: mIDH ICC drives progression through the accumulation of 2-HG, which interferes with metabolic and epigenetic processes such as the TET2, SRC kinase, and BET signaling pathways. Viable treatment options remain limited due to intratumoral heterogeneity and tumor evasion, which reduce both innate and cell-mediated responses. Despite these challenges, targeted therapies such as AG-120, dasatinib, JQ1, and olaparib have shown promise. Further investigations are necessary to understand the integrated nature of these biological pathways.

Works Cited:

1. Moris D, Palta M, Kim C, Allen PJ, Morse MA, Lidsky ME. Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin. 2023;73(2):198-222. doi:10.3322/caac.21759
2. Brindley PJ, Bachini M, Ilyas SI, et al. Cholangiocarcinoma. Nat Rev Dis Primers. 2021;7(1):65. doi:10.1038/s41572-021-00300-2
3. Wu MJ, Shi L, Merritt J, Zhu AX, Bardeesy N. Biology of IDH mutant cholangiocarcinoma. Hepatology. 2022;75(5):1322-1337. doi:10.1002/hep.32424
4. Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer. 2019;19(1):185. doi:10.1186/s12885-019-5391-0
5. Salati M, Caputo F, Baldessari C, et al. IDH Signalling Pathway in Cholangiocarcinoma: From Biological Rationale to Therapeutic Targeting. Cancers (Basel). 2020;12(11). doi:10.3390/cancers12113310
6. Xiang X, Liu Z, Zhang C, et al. IDH Mutation Subgroup Status Associates with Intratumor Heterogeneity and the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma. Adv Sci (Weinh). 2021;8(17):e2101230. doi:10.1002/advs.202101230
7. Wu MJ, Shi L, Dubrot J, et al. Mutant IDH Inhibits IFNγ-TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma. Cancer Discov. 2022;12(3):812-835. doi:10.1158/2159-8290.CD-21-1077
8. Luk IS, Bridgwater CM, Yu A, et al. SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma. Sci Transl Med. 2024;16(747):eadj7685. doi:10.1126/scitranslmed.adj7685
9. Cecchini M, Pilat MJ, Uboha N, et al. Olaparib in treatment-refractory isocitrate dehydrogenase 1 (IDH1)- and IDH2-mutant cholangiocarcinoma: Safety and antitumor activity from the phase 2 National Cancer Institute 10129 trial. Cancer. 2025;131(4):e35755. doi:10.1002/cncr.35755