biostudies-literatureUnknown12(11)Salati MBiliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an "orphan" to a "target-rich" disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.CancersE3310https://www.ebi.ac.uk/biostudies/studies/S-EPMC7696955biostudies-literatureIDH Signalling Pathway in Cholangiocarcinoma: From Biological Rationale to Therapeutic Targeting.PMC7696955Galassi BDominici MSalati MCaputo FBaldessari CGrossi FGhidini MfalseIDH Signalling Pathway in Cholangiocarcinoma: From Biological Rationale to Therapeutic Targeting.Biliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an "orphan" to a "target-rich" disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.2020-01-01T00:00:00Z2020 Nov2025-04-26T20:15:06.504Z2025-04-06T16:20:49.234ZS-EPMC76969553318251710.3390/cancers12113310