3.9 Article

Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors

期刊

NAR CANCER
卷 3, 期 2, 页码 -

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OXFORD UNIV PRESS
DOI: 10.1093/narcan/zcab018

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资金

  1. National Institutes of Health [R01 CA215453-02]
  2. America Association of Cancer Research [18-40-12-SULE]
  3. National Brain Tumor Society [2021]

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The study demonstrates the efficacy of ATR inhibitors against IDH1/2-mutant cells, particularly when combined with PARP inhibitors, showing potential anti-tumor activity in IDH1/2-mutant cancers.
Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, & alpha;-ketoglutarate (& alpha;KG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as 'BRCAness', which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1/2-mutant cancers and support the development of this combination in future clinical trials.

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