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

SIMPLE SUMMARY: Cholangiocarcinoma is among the most challenging cancers to treat, associated with poor prognosis both in the early and advanced setting. In the last decade, a deeper understanding of disease biology and cholangiocarcinogenesis has led to an increasing awareness of the molecular heterogeneity underpinning this disease and to the identification of several vulnerabilities to be targeted. To this end, the therapeutic exploitation of IDH mutations is the first successful example of precision medicine in cholangiocarcinoma. In the ClarIDHy trial, the small molecule inhibitor Ivosidenib provided a survival advantage in pretreated patients with IDH1-mutant cholangiocarcinoma, thus expanded the armamentarium against this molecular subtype of disease. 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.