IDH Signalling Pathway in Cholangiocarcinoma: From Biological Rationale to Therapeutic Targeting

Abstract

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.

Liver Transplantation for Unresectable Intrahepatic Cholangiocarcinoma: The Role of Sequencing Genetic Profiling

“…IDH converts isocitrate to α-ketoglutarate and produces NADPH, involved in many cellular processes. Mutated IDH causes the loss of its enzymatic activity with a gain of a neomorphic function to produce the R-enantiomer of 2-hydroxyglutarate (R-2-HG), which is considered to be an oncometabolite [ 32 ].…”

An Insight into the Novel Immunotherapy and Targeted Therapeutic Strategies for Hepatocellular Carcinoma and Cholangiocarcinoma

“…Additionally, there is a phase I clinical trial about the utilization of MET kinase inhibitors, such as tivantinib [ 65 ] for advanced CCA, or combined with a cytotoxic chemotherapeutic agent, gemcitabine with relative beneficial effect [ 66 ]. Another novel mutation in CCA is IDH1/2, in which selective inhibition, such as with AGI-6780 for iCCA, provided favorable results with good toleration [ 67 ].…”

The current state of molecular profiling in gastrointestinal malignancies

“…Isocitrate dehydrogenase (IDH) is a key enzyme in the tricarboxylic acid cycle and comprises 2 subtypes: IDH1, located in the peroxisomes and cytosol, and IDH2, located in the mitochondria [ 82 , 83 ]. In CCA, IDH1 mutations are found in 15–25% of cases, particularly in intrahepatic CCA.…”

“…IDH mutations generally lead to a gain-of-function that disrupts normal catalytic activity. The net effect is increased conversion of α-ketoglutarate to D-2-hydroxyglutarate, which leads to downstream cellular proliferation through pathways including DNA methylation and VEGFR [ 82 , 83 , 86 ].…”