Mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2 arise in a variety of malignancies and lead to the production of the oncometabolite (D)-2-hydroxyglutarate (2-HG). The recent approval by the FDA of mutant IDH1 and IDH2 (mIDH1/2) inhibitors in patients with mIDH1/2 relapsed/refractory acute myeloid leukemia (AML) underscores the clinical benefit of blocking production of 2-HG. Parallel investigations have indicated that IDH1/2 mutation leads to a ‘BRCAness’ phenotype and preferential sensitivity to PARP inhibition, ascribed to increased basal DNA damage and reduced capability of DNA damage repair. Significantly, these effects, and sensitivity to PARP inhibition, have been proposed to be 2-HG-dependent and thus potentially antagonistic with inhibition of mIDH1/2. In an effort to better understand the potential use of PARP inhibitors in mIDH cancers, we examined the effect of IDH mutations on the induction of DNA damage and regulation of DNA repair in IDH1-R132H mutant and wild type cell lines. We analyzed the levels of DNA damage by visualization of γH2AX by immunofluorescence and western blot and found, in agreement with previous work, that the presence of mutations in IDH1 correlates with higher basal DNA damage levels. However, in contrast to previous observations, we found that the reduction of 2-HG by treatment with mIDH1 inhibitors in vitro does not reverse this phenotype. Additionally, we observed that the presence of an IDH1 mutation provides reduction in homologous recombination efficiency, though not to the same extent as a cell lacking BRCA2. Furthermore, we failed to detect a heightened sensitivity to PARP inhibition alone in mIDH1 cells in cell-based assays as compared with the reduced viability observed for cells lacking BRCA2 when treated with PARP inhibitors. Similarly, we failed to observe any tumor growth inhibition in mIDH1 mouse xenografts treated with a PARP inhibitor. To account for this disconnect we examined large, publicly-available data sets to look for a ‘BRCAness’ genomic signature in AML, low grade glioma, and cholangiocarcinoma - all tumor types with a prevalence of IDH1 mutations. While we found a very minor fraction (<3%) of low-grade glioma carrying a mutational signature associated with DNA mismatch repair activity, we failed to find a ‘BRCAness’ signature in any of the three primary mIDH1 indications. Taken together, our data demonstrate that, while mIDH1 cells have increased basal levels of DNA damage, the reduction of 2-HG by selective mIDH1 inhibitors does not reduce the basal DNA repair deficiency in mIDH1 cells. Furthermore, the increase in DNA damage found in mIDH1 cells does not lead to heightened sensitivity to PARP inhibition in vivo.
Citation Format: Elia Aguado-Fraile, Christine Hudson, Taryn Sleger, Sebastien Ronseaux, Rohini Narayanaswamy, Sung Choe, Bin Wu, Peter Kalev, Brandon Nicolay. IDH1-R132H tumor cells are not robustly sensitive to PARP inhibition in a 2-HG dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3510.