Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives

Simple Summary Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are essential metabolic enzymes involved in the tricarboxylic acid (TCA) cycle. Several mutations in IDH genes have recently been described in many solid tumors, including glioma, cholangiocarcinoma, and chondrosarcoma. These mutations lead to neomorphic enzymatic activity affecting cancer pathogenesis. This review aims to summarize the diagnostic and prognostic role of IDH mutations and to provide an overview of the actual IDH inhibitor-based therapies used in various solid malignancies, outlining the findings of the most recent clinical trials and searching for future perspectives. Abstract The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included.