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Comment
. 2013 May 3;340(6132):558-9.
doi: 10.1126/science.1238523.

Cancer. Silencing a metabolic oncogene

Jiyeon Kim  1 , Ralph J DeBerardinis
Affiliations
Comment

Cancer. Silencing a metabolic oncogene

Jiyeon Kim et al. Science. .

Abstract

Small molecules inhibit a mutant enzyme confined to tumors, supporting therapeutic approaches that can reprogram metabolism in cancer.

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Figures

Figure 1
Figure 1. Reversing the perfect storm
Heterodimers of wild-type and mutant subunits of the metabolic enzymes IDH1/2 catalyze the production of (R)-2-hydroxyglutarate. Its accumulation impairs α-ketoglutarate–dependent dioxygenases, including those that modify DNA and histones (including the demethylation of 5-methylcytosine by TET-family hydroxylases and histone demethylases of the JmjC domain-containing family). This alters the epigenetic landscape, thereby blocking cell differentiation and promoting the acquisition of malignant features. Inhibitors (AGI-6780 and AGI-5198) that block (R)-2-hydroxyglutarate–producing IDH isoforms limit the growth of gliomaand AML-derived cancer cells.
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Comment on

  • (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible.
    Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley GS, Root DE, Ebert BL, Kaelin WG Jr. Losman JA, et al. Science. 2013 Mar 29;339(6127):1621-5. doi: 10.1126/science.1231677. Epub 2013 Feb 7. Science. 2013. PMID: 23393090 Free PMC article.
  • An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.
    Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK. Rohle D, et al. Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4. Science. 2013. PMID: 23558169 Free PMC article.
  • Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
    Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE. Wang F, et al. Science. 2013 May 3;340(6132):622-6. doi: 10.1126/science.1234769. Epub 2013 Apr 4. Science. 2013. PMID: 23558173

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