Year: 2021
Type: article
Abstract: 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, α-ketoglutarate (αKG), 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.
Source: NAR Cancer
Institution: Yale University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,040
Awards: Exploiting Mutant IDH1/2-induced Homologous Recombination Defects in Cancer, Institutional National Research Service Award, G7827448794, G8315287662, Dual-specificity phosphatase action in muscle disease, YALE CANCER CENTER CALABRESI IMMUNO-ONCOLOGY TRAINING PROGRAM, Targeting the DNA damage response with PARP and ATR inhibition to potentiate cytotoxicity and improve efficacy of immune checkpoint blockade in IDH mutant gliomas, Yale Clinical and Translational Science Award, Cancer Center Support Grant
OpenAlex ID: W3162010243