Abstract
Inhibitors of mutant IDH enzymes promote differentiation of leukemia and glioma cells.
Major finding: Inhibitors of mutant IDH enzymes promote differentiation of leukemia and glioma cells.
Concept: Mutant IDH enzymes may promote proliferation through nonepigenetic mechanisms.
Impact: Cancers with IDH mutations may be amenable to differentiation therapy with mutant IDH inhibitors.
Recurrent isocitrate dehydrogenase (IDH) mutations have recently been identified in several cancer types. These point mutations specifically affect IDH1 and IDH2 active site arginine residues and confer the ability to reduce α-ketoglutarate to R-2-hydroxyglutarate (2HG), an oncometabolite that competitively inhibits α-ketoglutarate–dependent enzymes, such as histone and DNA demethylases. To better understand the role of mutant IDH enzymatic activity in tumor maintenance, 2 groups evaluated the effects of selective mutant IDH1 and IDH2 inhibitors on cancer cells harboring IDH mutations. Wang and colleagues treated primary acute myeloid leukemia (AML) cells expressing the IDH2 R140Q mutant with AGI-6780, a molecule that allosterically inhibited mutant IDH2 with nanomolar potency but had little activity toward wild-type IDH2, IDH1, or other dehydrogenases. AGI-6780 specifically reduced 2HG to near-normal levels in a dose-dependent manner and induced differentiation of IDH2-mutant AML blasts. Rohle and colleagues developed a selective inhibitor of the IDH1 R132H mutant, which is frequently expressed in low-grade gliomas. This molecule, AGI-5198, potently inhibited IDH1 R132H but had no effect on wild-type IDH1 or wild-type or mutant IDH2. Treatment of IDH1-mutant glioma cells with AGI-5198 led to a dose-dependent decrease in 2HG levels and partial inhibition of colony formation in vitro and xenograft growth in vivo. Moreover, AGI-5198 induced expression of genes associated with astrocytic and oligodendrocytic differentiation and reduced repressive histone trimethylation marks at these gene promoters. However, AGI-5198 did not reverse DNA hypermethylation associated with IDH1 mutation, and AGI-5198 doses that were insufficient to reverse histone trimethylation still suppressed tumor growth, suggesting that the role of mutant IDH1 in tumor maintenance is not limited to its inhibitory effects on histone and DNA demethylases. Together, these studies provide insight into the role of mutant IDH enzymes in tumorigenesis and indicate that differentiation therapy may be achievable in cancers with IDH mutations.