Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer

Clark, Owen; Yen, Katharine; Mellinghoff, Ingo K.

doi:10.1158/1078-0432.ccr-13-1333

Cited by 178 publications

(143 citation statements)

References 71 publications

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“…As mentioned above, the IDH mutation in gliomas has considerable prognostic implications, where mutated LGG patients live ~ 2.3× longer [45] and mutated GBM patients live ~ 2.0–3.5× longer [17, 45] than IDH1 WT patients. Emerging evidence suggests that these tumors co-opt numerous different biological processes compared to their WT counterparts [18, 20–23]. One of these differentially adapted processes is tumor cell invasion.…”

Section: Discussionmentioning

confidence: 99%

“…The most commonly identified mutation is the IDH1 R132H gain-of-function mutation, which catalyzes the NADPH dependent reduction of α-ketoglutarate (α-KG) to produce the R enantiomer of 2-hydroxyglutarate (2-HG) [19]. In turn, 2-HG inhibits α-KG-dependent dioxygenases, with resultant downstream effects that mediate tumor cell interactions with the environment, collagen modification, responses to hypoxia, and immune evasion [18, 20–23]. IDH1 mutant GBMs are more likely to involve the frontal lobes, demonstrate less contrast enhancement, and produce less peritumoral changes on MRI [24].…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

et al. 2018

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The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2′-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

et al. 2018

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“…Subsequent studies revealed that IDH1 mutations occur in more than 70% of low grade gliomas and up to 20% of higher grade tumors (secondary glioblastoma multiforme; GBM), and approximately 10% of AML cases (3), 10% of cholangiocarcinoma (4), as well as in melanomas (5) and chondrosarcomas (6). Additionally, mutations were also identified in IDH2, the mitochondrial homolog of IDH1, in about 4% of gliomas and 10% of AMLs (3, 7). Nearly all known IDH1/2 alterations are heterozygous missense mutations that confer a neomorphic activity on the encoded enzymes, such that they convert α-KG to (R)-2HG (8).…”

Section: Introductionmentioning

confidence: 99%

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

et al. 2017

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2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, whereas the latter is produced under pathologic processes such as hypoxia. Here, we report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. This “BRCAness” phenotype of IDH mutant cells can be completely reversed by treatment with small molecule inhibitors of the mutant IDH1 enzyme, and, conversely, it can be entirely recapitulated by treatment with either 2HG enantiomer alone in cells with intact IDH1/2 proteins. We demonstrate IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR-deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.

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“…In lower-grade glioma, an analysis of clonality also suggests that IDH1 mutation is among the earliest events, and occurs before TP53 mutation in astrocytomas or loss of 1p/19q in astrocytomas and oligodendrogliomas (18–21). Based on these findings a series of mutant IDH1 inhibitors have been developed and are in clinical testing (22, 23). …”

Section: Introductionmentioning

confidence: 99%

Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis

Johannessen

Mukherjee

Viswanath

et al. 2016

Molecular Cancer Research

100

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Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. While mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown. To address this question we exposed immortalized (p53/pRb-deficient), untransformed human astrocytes to the mutant IDH1 inhibitor AGI-5198 prior to, concomitant with, or at intervals after, introduction of transforming mutant IDH1, then measured effects on 2-HG levels, histone methylation (H3K4me3, H3K9me2, H3K9me3 or H3K27me3) and growth in soft-agar. Addition of AGI-5198 prior to, or concomitant with, introduction of mutant IDH1 blocked all mutant IDH1-driven changes including cellular transformation. Addition at time intervals as short as 4 days following introduction of mutant IDH1 also suppressed 2-HG levels, but had minimal effects on histone methylation, and lost the ability to suppress clonogenicity in a time-dependent manner. Furthermore, in two different models of mutant IDH1-driven gliomagenesis, AGI-5198 exposures that abolished production of 2-HG also failed to decrease histone methylation, adherent cell growth, or anchorage-independent growth in soft-agar over a prolonged period. These studies show although mutant IDH1 expression drives gliomagenesis, mutant IDH1 itself rapidly converts from driver to passenger. Implications Agents that target mutant IDH may be effective for a narrow time and may require further optimization or additional therapeutics in glioma.

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Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer

Cited by 178 publications

References 71 publications

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis

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