D-2-HG is a metabolite that is absent in normal cells. The production of large quantities of D-2-HG inevitably depletes a substantial amount of carbohydrate from the Krebs cycle. Several hallmark studies have demonstrated the presence of depleted metabolic pathways in
IDH-mutated cells. For example, glutamate metabolism is greatly altered in
IDH mutant glioma, as mentioned before. The glutamate level is significantly lower in
IDH mutant cancers, which leads to an increased dependence on glutaminolysis to compensate for the metabolism
[29][89][90][91]. Several studies have reported that a blockade of glutaminase activity results in the suppression of
IDH mutant glioma and AML. Seltzer et al. and Emadi et al.
[89][90] reported that bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES), an inhibitor of glutaminase, selectively suppresses tumor growth in
IDH mutant glioma and AML by targeting the fragile glutamine metabolism. Another glutaminase inhibitor (CB-839) was also reported to induce selective radio-sensitivity in
IDH mutant cancers
[29] and terminal differentiation in
IDH mutant AML
[91]. An ongoing phase I clinical trial is investigating the side effects and the best dose of CB-839, in combination with radiation therapy and temozolomide, for treating
IDH-mutated diffuse or anaplastic astrocytoma (NCT03528642). In addition,
IDH mutations lead to the depletion of NAD
+ because of the increased methylation of the promoter region of
NAPRT1, the rate-limiting enzyme in NAD
+ biosynthesis, and suppression of the expression of NAPRT1. This renders the
IDH mutant glioma vulnerable to inhibition through the nicotinamide phosphoribosyltransferase (NAMPT) catalyzed NAD
+ salvage pathway
[92]. Moreover, Tateishi et al.
[93] showed that NAMPT inhibitors further sensitized
IDH mutant cancer cells to alkylating agents, such as temozolomide, as PARP activation consumes NAD
+ during the base excision repair of chemotherapy-induced DNA damage. With the substantially exhausted metabolic pathways, distinctive metabolic vulnerabilities are established in
IDH-mutated malignancies. Effectively targeting these metabolic pathways may induce selective cytotoxicity to cancer cells, but a lesser extent than that occurs in normal somatic cells with an intact metabolic network.