ReviewCELL BIOLOGY

Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease

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Science Advances  22 May 2019:
Vol. 5, no. 5, eaaw4543
DOI: 10.1126/sciadv.aaw4543

Figures

  • Fig. 1 Subcellular localization and chemical reactions catalyzed by wild-type IDH and tumor-derived IDH mutant enzymes.

  • Fig. 2 Deregulation of IDH enzymatic activity is associated with human disease.

    Upward or downward pointing arrows indicate overexpression or downregulation of wild-type IDHs (shown in blue), respectively.

  • Fig. 3 Compensation for wild-type IDH1 loss of function in GBM tumors characterized by high glutamate flux to support TCA and lipid biosynthesis activities.

    AA, amino acids; Ac-CoA, acetyl–coenzyme A; CIT, citrate; Glu, glutamate; GLUD, glutamate dehydrogenase; OE, overexpression; Pyr, pyruvate.

Tables

  • Table 1 Synthetic lethal interaction of IDH compromise and the development of combinatorial treatment regimens.

    TMZ, temozolomide; BPTES, bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide; Mcl-1, induced myeloid leukemia cell differentiation protein; Bcl-xL, B cell lymphoma–extra large; RT, radiotherapy; MYC, myelocytomatosis; BET, bromo- and extra-terminal domain; CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

    IDH mutant
    disease/cell lines
    Synthetic lethal interactionTherapeutic regimenReference
    GliomaReduction in NAD+ levels and vulnerability to NAD+ depletionNAMPT inhibitor (GMX-1778)(89)
    GliomaPARP-mediated DNA repair after chemotherapy-induced
    DNA damage
    Temozolomide and NAMPT inhibitor(104)
    MPNsGain-of-function mutations in JAK/STATCo-inhibition of JAK2 and mutant IDH1 and IDH2(106)
    AML(R)-2HG inhibits cytochrome c oxidase, lowering the threshold
    for apoptosis induction in response to Bcl-2 inhibition
    Bcl-2 inhibitor ABT-199(107)
    ICCsIncreased sensitivity to inhibition of nonreceptor tyrosine
    kinase SRC
    Dasatinib(108)
    Mammary epithelialIDH1-R132H cells have compromised ability to obtain energy
    from major sources of cellular carbon and are dependent
    on glutamine
    Metformin alone or with glutaminase inhibitor
    BPTES or IDH1-R132H inhibitor AG5918
    (125)
    Glioblastoma and glioma(R)-2HG results in low levels of Mcl-1 and increased sensitivity
    to inhibition of Bcl-xL
    Bcl-xL inhibitor ABT-263(126)
    GlioblastomaOverexpression of IDH1-R132H enhanced the cytotoxic effect
    of radiation through altered ROS metabolism
    Radiation therapy(127)
    Primary low-grade gliomasMYC pathway is activated in patient-derived tumors and
    makes cells sensitive to BET inhibitors
    Brd inhibitors JQ1 and GS-626510(128)
    Glioblastoma(R)-2HG inhibits ALKBH2 and ALKBH3 DNA repair enzymes
    sensitizing cells to alkylating agents
    Alkylating agents busulfan, procarbazine, CCNU,
    or vincristine
    (129)
    GlioblastomaGlutaminase converts glutamine to glutamate, then converted
    to αKG and then to 2HG
    Glutaminase inhibitor BPTES(130)
    Glioma2HG inhibits BCAT1 and BCAT2, which are used by the cells to
    convert BCAA into glutamate. This makes the cells even
    more reliant on glutaminases for glutamate biosynthesis
    Glutaminase inhibitor CB-839 and RT or TMZ(58)
    AMLIDH1-R132H cells have increased ACACA gene expression
    compared to wild type
    ACACA inhibitor TOFA(131)
  • Table 2 IDH mutant inhibitors.

    N/A, not applicable; ND, not determined.

    DrugTargetIC50Cancer indicationClinical trial
    number
    MutantWild-type/mutant
    heterodimer
    Wild type
    AGI-5198IDH1R132H0.07 μMN/A>100 μMN/A
    AG-120IDH1R132H12 nM12 nM71 nMLow-grade glioma
    Hematologic
    malignancies
    Advanced
    cholangiocarcinoma
    NCT02481154
    NCT03343197
    NCT03071770
    NCT02074839
    NCT03503409
    NCT02989857
    NCT03173248
    NCT02632708
    NCT02677922
    NCT03471260
    NCT03564821
    AGI-6780IDH2R140Q170 nM120 nM2.7 μMN/A
    AG-221IDH2R140Q0.32 μM0.31 μM39.8 μMHematologic
    malignancies
    NCT03515512
    NCT03383575
    NCT03683433
    NCT02577406
    NCT01915498
    NCT02387866
    NCT02632708
    NCT02273739
    AG-881Pan-specific
    mutant IDH
    31.9 nM (IDH1R132H)
    31.7 nM (IDH2R140Q)
    N/AN/AHematological
    malignancies
    Low-grade glioma
    Advanced solid tumors
    NCT02492737
    NCT02481154
    NCT03343197
    BAY1436032IDH1R132H15 nMN/A20 μMAdvanced malignanciesNCT02746081
    NCT03127735
    GSK321IDH1R132H4.6 nMN/A46 nMN/A
    GSK864IDH1R132H15.2 nMN/A466.5 nMN/A
    IDH305IDH1R132H0.027 nMN/A6.14 μMHematological
    malignancies
    NCT02381886
    MRK-AIDH1R132H5 nMN/AN/DN/A

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