Isocitrate dehydrogenase (IDH) as target for anticancer therapy in brain and gastrointestinal cancers

Abstract

Isocitrate dehydrogenase (IDH) enzyme system plays a central role in cellular metabolism, growth, and differentiation, and its mutations are associated with alterations of the cell cycle and production of oncometabolites, promoting tumor development. In this narrative review, we provide an overview of the current evidence on the therapeutic use of IDH inhibitors in IDH mutant gliomas and gastrointestinal cancers, focusing on cholangiocarcinoma (CCA) and colorectal cancer (CRC). Recent clinical studies showed promising data for IDH-targeted therapy in reducing tumor volume and led to the Food and Drug Administration (FDA) approval of ivosidenib for previously treated metastatic biliary tract cancers and vorasidenib for patients with IDH mutant low-grade gliomas following surgery. In addition, we discuss the emerging, although still limited, evidence regarding IDH mutations in colorectal cancer. Herein, we describe the characteristics of the FDA-approved and other investigational IDH-targeted drugs, evaluating the most recent clinical studies on targeting IDH genomic alterations in the treatment of gliomas and cholangiocarcinoma; we also provide insight into factors involved in resistance to IDH inhibition and potential strategies to overcome resistance mechanisms. Finally, we examine the major challenges facing IDH targeted therapy, including primary and acquired resistance, while highlighting future research directions such as next-generation IDH inhibitors, combination strategies, potential biomarkers, and the integration of molecular profiling into precision oncology to improve clinical outcomes.