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

• Published in: NAR cancer Vol. 3; no. 2; p. zcab018
• Main Authors: Sule, Amrita, Van Doorn, Jinny, Sundaram, Ranjini K, Ganesa, Sachita, Vasquez, Juan C, Bindra, Ranjit S
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.06.2021
• Subjects: Editor's Choice; Nucleic Acid-Based Cancer Therapeutics
• ISSN: 2632-8674; 2632-8674
• DOI: 10.1093/narcan/zcab018

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. Graphical Abstract Graphical Abstract In the presence of elevated genomic instability in HR-deficient IDH1/2 mutant cells and accumulation of PARP-inhibitor mediated DNA breaks, ATR inhibition abrogates S-phase arrest and causes apoptosis by premature mitotic entry (Created using Biorender.com).