Abstract 3637: Sensitivity of breast cancer cell lines with distinct genotypes to poly(ADP-ribose) polymerase inhibitor or in combination with DNA damaging agents

Abstract

Abstract Poly(ADP-ribose) polymerase (PARP) is required for the repair of single-strand DNA nicks and BRCA1/2 proteins are directly involved in the repair of DNA double-strand breaks through homologous recombination (HR). Recent studies have demonstrated that PARP inhibitors administered as single agents are active in 33 to 38% of BRCA-deficient advanced breast and ovarian cancer patients. However, the resistant mechanisms for the two thirds of patients with genetically-defined BRCA deficiency who did not respond to anti-PARP agents are largely undefined. The aim of this study was to test sensitivity of breast cancer cell lines with distinct genotypes to a PARP inhibitor alone or in combination with DNA damaging agents (topotecan and carboplatin). Methods: HCC1428 (BRCA2-mutant [2135basepair.del], but HR-competent breast adenocarcinoma); MDA-MB-231 (triple [ER, PR and HER2]-negative, BRCA-wildtype breast adenocarcinoma); and MCF-7 (BRCA-wildtype breast ductal carcinoma) cells were treated with carboplatin (1 μM), topotecan (10 nM), or veliparib (1 μM; ABT-888) alone or in combinations consisting of veliparib with topotecan or carboplatin for 24h. The survival of cancer cells was evaluated by clonogenic assays. Differences in cell survival (colony numbers) between vehicle-treated and veliparib-, DNA damaging agent-, or combination-treated were evaluated with unpaired t-tests and P values are two-sided. Results: Veliparib plus topotecan compared to topotecan alone markedly reduced the survival of MDA-MB-231 (mean ± SD; 36 ± 3 vs. 141 ± 4; P ≤ 0.01), MCF-7 (6 ± 1 vs. 25 ± 0.8; P ≤ 0.01), HCC1428 (10 ± 2 vs.29 ± 6; P = 0.04). The combination of veliparib and carboplatin versus carboplatin alone also reduced the survival of MDA-MB-231 (133 ± 2 vs. 477 ± 138; P ≤ 0.01), MCF-7 (48 ± 5 vs. 60 ± 2; P = 0.07) and HCC1428 (184 ± 6 vs. 260 ± 14; P ≤ 0.01). Veliparib has single agent activity in MCF-7 (53 ± 8 vs. 80 ± 4; P = 0.02) but not in BRCA2-mutant HCC1428 (259 ± 10 vs. 257 ± 13; P = 0.83) or triple-negative MDA-MB-231 (121 ± 2 vs. 104 ± 6; P = 0.54) cells. Conclusions: Veliparib enhances breast cancer cell death induced by DNA damaging agents. It has single agent activity in BRCA-wildtype MCF-7 cells, suggestive of other mechanisms of response to PARP inhibition in addition to BRCA deficiency. The BRCA2-mutant line HCC1428 is resistant to veliparib or carboplatin treatment alone but sensitive to topotecan alone or in combination with veliparib. The latter may provide an alternative for the management of PARP inhibitor- or platinum-resistant BRCA-mutant tumors. The underlying mechanisms of sensitivity or resistance to the PARP inhibitor alone or to the PARP inhibitor plus DNA damaging agents are under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3637.