Molecular and morphological changes induced by ivosidenib correlate with efficacy in mutant- IDH1 cholangiocarcinoma

Future Oncol. 2021 Jun;17(16):2057-2074. doi: 10.2217/fon-2020-1274. Epub 2021 Mar 12.


Background: IDH1 mutations occur in approximately 13% of intrahepatic cholangiocarcinomas (IHCCs). The oral, targeted, mutant IDH1 (mIDH1) inhibitor ivosidenib (AG-120) suppresses production of the oncometabolite D-2-hydroxyglutarate, promoting disease stabilization and improved progression-free survival (PFS) in mIDH1 IHCC. Materials & methods: Harnessing matched baseline and on-treatment biopsies, we investigate the potential mechanisms underlying ivosidenib's efficacy. Results: mIDH1 inhibition leads to decreased cytoplasm and expression of hepatocyte lineage markers in patients with prolonged PFS. These findings are accompanied by downregulation of biliary fate, cell cycle progression and AKT pathway activity. Conclusion: Ivosidenib stimulates a hepatocyte differentiation program in mIDH1 IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors. Clinical trial registration: NCT02073994 (

Keywords: cholangiocarcinoma; drug mechanisms; gastrointestinal cancers; genetic profiling; hepatic differentiation; isocitrate dehydrogenase; ivosidenib; tumor biopsy.

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Bile Duct Neoplasms / drug therapy*
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology
  • Cell Differentiation / drug effects
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology
  • Clinical Trials, Phase I as Topic
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / genetics*
  • Mutation*
  • Neoplasm Grading
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / pharmacology*
  • Survival Rate
  • Treatment Outcome


  • Antineoplastic Agents
  • Pyridines
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • ivosidenib
  • Glycine

Associated data