Metabolic consequences of oncogenic IDH mutations

Abstract

Specific point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in a variety of cancers, including acute myeloid leukemia (AML), low-grade gliomas, and chondrosarcomas. These mutations inactivate wild-type enzymatic activity and convey neomorphic function to produce D-2-hydroxyglutarate (D-2HG), which accumulates at millimolar levels within tumors. D-2HG can impact α-ketoglutarate-dependent dioxygenase activity and subsequently affect various cellular functions in these cancers. Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors. As IDH1 and IDH2 represent key enzymes within the tricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism. The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future. Here we review how IDH1 and IDH2 mutations influence cellular metabolism, epigenetics, and other biochemical functions, discussing these changes in the context of current efforts to therapeutically target cancers bearing these mutations.

Mitochondria and Cancer

“…There are many α-ketoglutarate-dependent enzymes, particularly dioxygenases, and 2-HG is a competitive inhibitor of these enzymes, particularly, hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs), JmjC domain- containing histone demethylases (part of the JMJD family) and the ten-eleven translocation (TET) family of 5methyl cytosine (5mC) DNA hydroxylases. Oncometabolite-driven changes in the epigenome suppress differentiation and promote proliferation (Dang et al, 2009; Lu and Thompson, 2012; Parker and Metallo, 2015). 2-HG has also been found to inhibit the PHDs that degrade the HIFs and may thereby have a role in cancer.…”

Pheochromocytoma: Gasping for Air

“…D2HG is structurally very similar to α-KG and glutamate; this similarity results in the competitive inhibition of α-KG-dependent dioxygenases [123]. Unlike succinate and fumarate, the effect of D2HG on PHDs is not completely clear since there is evidence of both inhibition [123,124] and activation of PHDs [125,126]; reviewed in [127]. According to the work of Williams et al [128], mutant IDH1 expression in gliomas was not sufficient to stabilize HIF-1α.…”

“…But there is evidence that accumulation of D2HG is associated with epigenetic changes, disruption of defense mechanisms against ROS, and changes in redox homeostasis. Mechanisms of its involvement in tumorigenesis are not fully understood yet but are thought to be based on epigenetic modifications that result in differential expression of genes involved in cell proliferation, changes in HIF-α levels, as well as aberrant extracellular matrix structures induced by changes in collagen synthesis [39,45,127]. Further studies are needed to fully explore metabolic and physiological defects present in IDH-mutated tumors as well as their consequences and roles in tumorigenesis.…”

In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors

“…The role of 2-HG as an oncometabolite has been linked to epigenetic changes through the inhibition of α -KG dependent dioxygenases and demethylases, which has been hypothesized to be a driver for carcinogenesis (Lu et al, 2012; Xu et al, 2011b; Yen et al, 2010). In addition, the redirection of α -KG flux from normal reductive metabolism in the TCA cycle towards 2-HG generation has been suggested to dysregulate other metabolic fluxes and disrupt redox balance (Ohka et al, 2014; Parker and Metallo, 2015; Tateishi et al, 2015). Multiple cancers have been identified to carry an IDH1 or IDH2 mutation including low-grade gliomas, secondary glioblastomas (GBM), chondrosarcomas, and acute myelogeneous leukemia (AML) (de Botton et al, 2016).…”