Open AccessMolecular and morphological changes induced by ivosidenib correlate with efficacy in mutant-IDH1 cholangiocarcinoma
Author(s) -
Elia Aguado-Fraile,
Anna M. Tassinari,
Yuko Ishii,
Carlie S. Sigel,
Maeve A. Lowery,
Lipika Goyal,
Camelia Gliser,
Longying Jiang,
Shuchi S. Pandya,
Bin Wu,
Nabeel Bardeesy,
Sung Choe,
Vikram Deshpande
Publication year - 2021
Publication title -
future oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.857
H-Index - 72
eISSN - 1744-8301
pISSN - 1479-6694
DOI - 10.2217/fon-2020-1274
Subject(s) - idh1 , isocitrate dehydrogenase , medicine , cancer research , intrahepatic cholangiocarcinoma , downregulation and upregulation , mutant , oncology , biology , gene , enzyme , genetics , biochemistry
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 m IDH1 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 m IDH1 IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors. Clinical trial registration: NCT02073994 ( ClinicalTrials.gov )