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.

Keywords: IDH; biliary cancer; cholangiocarcinoma; gallbladder cancer; ivosidenib; precision medicine; targeted therapy.

Figure 1

Anatomical sub-classification of biliary tract cancers. Based on the anatomical site of origin within the biliary tree, biliary tract cancers are subdivided into intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC).

Figure 2

Normal and deregulated isocitrate dehydrogenase (IDH) signaling in cancer. Abbreviations: wt IDH1/2, wild-type isocitrate dehydrogenases 1 and 2; mut IDH1/2, mutant isocitrate dehydrogenases 1 and 2; TET, ten-eleven translocation.