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

Abstract

2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, whereas the latter is produced under pathologic processes such as hypoxia. Here, we report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. This “BRCAness” phenotype of IDH mutant cells can be completely reversed by treatment with small molecule inhibitors of the mutant IDH1 enzyme, and, conversely, it can be entirely recapitulated by treatment with either 2HG enantiomer alone in cells with intact IDH1/2 proteins. We demonstrate IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR-deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.

The DNA damage response pathway in normal hematopoiesis and malignancies

“…Most mutations in IDH1 confer a neomorphic activity on the enzymes, such that they convert α-ketoglutarate to (R)-2-hydroxyglutarate, which is considered an oncometabolite having effects on chromatin methylation and cellular differentiation [55]. Mutant IDH1 inhibits TET2, an enzyme involved in cytosine demethylation, resulting in disrupted DNA methylation and differentiation.…”

“…Most recently, the finding that cells harboring mutant IDH1 (and IDH2) markedly repress the repair of DNA damage by homologous recombination has provided a mechanistic evidence explaining the enhanced chemosensitivity and radiosensitivity of IDH1 mutant tumors. Moreover, since HR defects induce synthetic lethal interactions with PARP inhibitors (e.g., olaparib) or ATR inhibitors (e.g., VE-822), studies performed with patient-derived AML cells harboring IDH1 mutations causing HR suppression and DDR defects have shown that these cells are, compared to matched IDH1 wild-type cases, highly vulnerable to PARP inhibitors and ionizing radiation [55]. The vulnerability to PARP inhibition may thus be therapeutically exploited in the case of IDH1-mutant HR-defective AML.…”

IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

“…We have shown that this response is mediated by d -2HG accumulation, which sensitizes cells to irradiation (IR), whereas inhibition of IDH1 MUT reduces oxidative stress in IDH1 MUT cells and thus protects cells against IR (15). Similarly, patients with IDH1 MUT cancers may respond well to cytotoxic treatment (6, 10, 16–18), including cisplatin [ cis -diamminedichloroplatinum(II)] (13, 19). However, the mechanism that induces cisplatin sensitivity in IDH1 MUT cancers is still unknown.…”

Basic Science in Oncology: Year 2017 Overview

“…Это, в свою очередь, приводит к фено-типу «BRCAness» -инактивации модуля репарации ДНК, использующего в своей работе гомологичную рекомбинацию. Чувствительность таких опухолей к ингибиторам PARP уже продемонстрирована в много-численных взаимодополняющих экспериментах [30].…”