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

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.

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

“…Here, we confirmed the presence of γH2AX after the ATRi monotherapy, PARPi:ATRi and PARPi:CHK1i combined therapy in PEO-1 cells. Our findings are consistent with previous studies [ 53 , 63 ]. Furthermore, consistent with a study by Huntoon et al, we found that γH2AX levels were increased after ATRi and CHK1i treatment alone or in combination with PARPi in BRCA MUT and BRCA WT cells [ 64 ].…”

Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma

“…It could be interesting to mechanistically understand the role of MMR and ATR in PARP signaling by treating with PARP inhibitors and ATR inhibitors. Recently published work from our laboratory showed that PARP and ATR inhibitors synergize in the common glioblastoma mutation in isocitrate dehydrogenase 1/2 (IDH1/2), so perhaps MMR-deficiencies may also benefit from this combination 43 . Ongoing work in our laboratory continues to investigate the role of these various therapeutics in combination with ATR inhibitors in MMR-deficient cells.…”

Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development

“…Also, as per preliminary findings, olaparib has been found to be safe as well as effective in IDH1/2-mutant mesenchymal sarcoma condition ( Eder et al, 2021 ). Another in vitro research has evaluated the effect of PARP inhibitors in combination with ATR inhibiting molecules in IDH1/2-mutant cells and suggested that this combination therapy elevates the premature mitotic entry in the presence of IDH1/2 mutations ( Sule et al, 2021 ). Various clinical studies are still ongoing in different phases in which PARP inhibitors are used in IDH mutated glioma patients.…”