Abstract 3633: Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation

Abstract

Abstract Loss or inhibition of Poly(ADP-ribose) polymerase 1 (PARP1) activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DNA double-strand breaks (DSBs) by the cellular replication and/or transcription machinery. Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair (HRR) of DNA DSB. In BRCA-positive cells, DSBs are repaired by HRR, but they cannot be properly repaired in BRCA-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death. The role of PARP1 in the DNA damage response promoted the development of PARP inhibitors (PARPi) as chemo- and radio-sensitizers for the treatment of cancers harboring mutations in the BRCA genes. However, inherited BRCA1 or BRCA2 mutations account for 5-10% of breast cancers and 10-15% of ovarian cancers. Hence, a low frequency of BRCA1 loss in non-hereditary tumors can limit the clinical use of this approach. Our recent work revealed significant down-regulation of BRCA1 gene expression by nitric oxide donors (NO-d) (Yakovlev, 2013). Hence, we assumed that combination of NO-d with PARP inhibitors could be effective in sensitization of the BRCA1-positive tumors to DNA-damaging therapy. We identified the optimal concentrations of PARPi ABT-888 at 20μM and NO-d SNAP at 200μM, which don't affect cell survival, but effectively block PARP1 activity or BRCA1 expression accordingly. Next, cancer cell lines were pretreated with ABT-888 or SNAP, or with they combination and irradiated. Survival curves were determined by clonogenic assay. Our preliminary data demonstrates significant radiosensitization when combining an NO-d with a PARPi in BRCA1 positive tumor cell lines (Table 1). We plan to test this drug combination on the additional cancer cell lines and on animal models for sensitization to ionizing radiation and to the different chemotherapeutic agents. Table 1.Clonogenic assay for A-549 and MDA-MB-231 cell lines: survival fraction.IR (Gy)02468A-549Control1.00±0.0380.55±0.0450.23±0.0360.09±0.0070.0242±0.004ABT-8881.00±0.0650.49±0.0310.18±0.0350.05±0.0040.0076±0.001SNAP0.97±0.0850.43±0.0450.16±0.0330.04±0.0080.0091±0.002ABT-888 + SNAP0.71±0.0750.24±0.0420.05±0.0070.01±0.0020.0014±0.0003MDA-MB-231Control1.00±0.0630.44±0.0380.15±0.0270.039±0.0070.0078±0.0007ABT-8880.85±0.0520.28±0.0170.07±0.0090.012±0.0020.0015±0.0005SNAP1.03±0.0380.3±0.0430.10±0.0080.020±0.0040.0034±0.0007ABT-888 + SNAP0.49±0.0660.12±0.0170.02±0.0070.002±0.00040.00013±0.0001 Citation Format: Aaron Wilson, Vasily A. Yakovlev. Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3633. doi:10.1158/1538-7445.AM2015-3633