IDH1

  • Isocitrate dehydrogenase 1 (IDH1)
  • Gene Location: chromosome 2 (2q34)

IDH1 Biology

  • The IDH1 gene, located on chromosome 2 (2q34), encodes the IDH1 enzyme, a dimeric cytosolic NADP-dependent isocitrate dehydrogenase.1
  • The IDH1 enzyme catalyzes the conversion of alpha-ketoglutarate to D-2-hydroxyglutarate (2-HG), a metabolite that plays a key role in chromatin regulation and cellular differentiation.2

Etiology and Epidemiology

  • Activating mutations in the IDH1 gene result in elevated accumulation of 2-HG, disrupting normal differentiation, leading to the buildup of hepatic progenitor cells and contributing to malignant transformation into intrahepatic cholangiocarcinoma (CCA).2
  • IDH1 mutations have been identified in approximately 10% to 20% of intrahepatic CCAs but are rare in other anatomical subsites.3-5
  • The most common IDH1 mutations in intrahepatic CCA occur at codon 132 (R132X).6

Testing for IDH1 Mutations

  • When to Test: Patients with unresectable or metastatic biliary tract cancers (BTCs) who are eligible for systemic therapy should undergo comprehensive molecular profiling at the time of diagnosis.6
  • Available Testing Methods: Testing for IDH1 mutations can be conducted through tumor next-generation sequencing (NGS) using a multigene panel or via hotspot mutation analysis. Additionally, cell-free DNA (cfDNA) testing is capable of detecting IDH1 hotspot mutations.6
  • Guideline Recommendations for Testing: The National Comprehensive Cancer Network (NCCN) guidelines recommend testing for IDH1 mutations in patients with unresectable or metastatic intrahepatic or extrahepatic CCA and advise considering this testing for those with unresectable or metastatic gallbladder cancer.6

IDH1 Targeted Therapy

  • Approved Agents: On August 25, 2021, the FDA approved ivosidenib for the treatment of locally advanced or metastatic CCA with an IDH1 mutation, the first and only IDH1-targeted therapy. Approval was based on the findings from study AG120-C-005 (NCT02989857), which evaluated ivosidenib in 185 patients with locally advanced or metastatic CCA with an IDH1 mutation who had progressed on 1 or 2 prior regimens, including at least 1 gemcitabine- or 5-flurouracil-containing regimen.7
  • Mechanism of Action: Ivosidenib is a small molecule inhibitor that specifically binds to and inhibits the mutant IDH1 enzyme that is responsible for converting alpha-ketoglutarate to 2-HG. By lowering 2-HG levels, ivosidenib helps restore normal cellular differentiation and can reverse the effects of the IDH1 mutation. This process may slow the growth of cancer cells and promote a more normal cellular phenotype.8

Learn more about Ivosidenib >

References

  1. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Isocitrate dehydrogenase, NADP(+), 1; IDH1. MIM Number: 147700. Updated April 17, 2024. Accessed October 4, 2024. https://www.omim.org/entry/147700
  2. Aguado-Fraile E, Tassinari A, Ishii Y, et al. Molecular and morphological changes induced by ivosidenib correlate with efficacy in mutant-IDH1 cholangiocarcinoma. Future Oncol. 2021;17(16):2057-2074. doi:10.2217/fon-2020-1274
  3. Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;18(11):2780-2794. doi:10.1016/j.celrep.2017.02.033
  4. Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol. 2019;10(4):751-765. doi:10.21037/jgo.2019.03.10
  5. Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016;122(24):3838-3847. doi:10.1002/cncr.30254
  6. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 4.2024. Accessed October 4, 2024. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
  7. FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma. Updated February 1, 2022. Accessed October 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-advanced-or-metastatic-cholangiocarcinoma
  8. TIBSOVO (ivosidenib). Prescribing information. Servier Pharmaceuticals LLC; 2023. https://www.tibsovopro.com/pdf/prescribinginformation.pdf