Agios Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Future Oncol. 2021 Jun;17(16):2057-2074. doi: 10.2217/fon-2020-1274. Epub 2021 Mar 12.
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 IHCC. Harnessing matched baseline and on-treatment biopsies, we investigate the potential mechanisms underlying ivosidenib's efficacy. 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. Ivosidenib stimulates a hepatocyte differentiation program in m IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors. NCT02073994 (ClinicalTrials.gov).
突变发生在约 13%的肝内胆管癌（IHCC）中。口服、靶向、突变 IDH1（mIDH1）抑制剂ivosidenib（AG-120）抑制致癌代谢物 D-2-羟基戊二酸的产生，在 mIHCC 中促进疾病稳定和无进展生存期（PFS）的改善。利用匹配的基线和治疗中活检，我们研究了ivosidenib 疗效的潜在机制。mIDH1 抑制导致具有延长 PFS 的患者的细胞质和肝细胞谱系标志物表达减少。这些发现伴随着胆管命运、细胞周期进展和 AKT 途径活性的下调。ivosidenib 在 mIHCC 中刺激肝细胞分化程序，这种表型与临床获益相关。mIDH1 抑制可能成为实体瘤基于分化的治疗范例。NCT02073994（ClinicalTrials.gov）。
