What question did this study set out to answer?

To investigate whether neomorphic IDH1 and IDH2 mutations and their oncometabolite 2-hydroxyglutarate impair homologous recombination and create targetable vulnerabilities to PARP inhibitors.

February 1, 2017Science Translational Medicine

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

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To investigate whether neomorphic IDH1 and IDH2 mutations and their oncometabolite 2-hydroxyglutarate impair homologous recombination and create targetable vulnerabilities to PARP inhibitors.
Assayed homologous recombination competency and PARP inhibitor sensitivity in cells harboring mutant IDH1/2 or exposed exogenously to (R)- and (S)-enantiomers of 2-hydroxyglutarate.
Evaluated the reversal and recapitulation of the DNA repair defect using small-molecule mutant IDH1 inhibitors in primary patient-derived glioma cell cultures and in vivo tumor xenografts.
Mutant IDH1/2 enzymes and both 2-hydroxyglutarate enantiomers induced a homologous recombination defect ('BRCAness') that rendered cancer cells hypersensitive to PARP inhibitors.
Small-molecule inhibitors against mutant IDH1 completely reversed the homologous recombination deficiency, while exogenous 2-hydroxyglutarate alone recapitulated the defect in wild-type cells.
Mutant IDH1-driven PARP inhibitor sensitivity was confirmed across primary patient-derived glioma cell models and genetically matched tumor xenografts in vivo.

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Implication

Preclinical study demonstrates that mutant IDH impairs homologous recombination and confers PARP inhibitor sensitivity in glioma models, suggesting a synthetic lethal strategy.

Cite This Study

Sulkowski et al. (2017) studied this question.

synapsesocial.com/papers/6a0370aefb1d234f482e6b07 https://doi.org/10.1126/scitranslmed.aal2463

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Implication

Preclinical study demonstrates that mutant IDH impairs homologous recombination and confers PARP inhibitor sensitivity in glioma models, suggesting a synthetic lethal strategy.

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

Key Points

Discussion

Implication

Cite This Study

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

Key Points

Discussion

Implication

Cite This Study

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