Targeting isocitrate dehydrogenase mutations (IDH) in AML: wielding the double-edged sword of differentiation.

Targeting isocitrate dehydrogenase mutations (IDH) in AML: wielding the double-edged sword of differentiation. Curr Cancer Drug Targets. 2020 Apr 24;: Authors: Becker JS, Fathi AT Abstract The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2-hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical ef...
Source: Current Cancer Drug Targets - Category: Cancer & Oncology Authors: Tags: Curr Cancer Drug Targets Source Type: research