Abstract 4846: Targeting BRCA1-mutated cancer cells with elesclomol

Abstract

Abstract The breast cancer susceptibility gene 1 (BRCA1) encodes a tumor-suppressor protein that maintains genetic stability through DNA damage response pathways. Specifically, BRCA1 has a well-established role in double-strand DNA break repair, and emerging evidence supports a role for BRCA1 in repair of oxidative DNA damage via the base-excision repair (BER) pathway. We and others have shown that cells with mutant/deficient BRCA1 harbor defective BER of oxidative DNA damage. Interestingly, defective BER of oxidative DNA damage in breast cancer cells rendered sensitivity to elesclomol, an experimental therapeutic that induces reactive oxygen species to levels beyond a viable threshold. Given that BRCA1-mutated cancers associate with a poor prognosis and are in need of targeted treatment options, we hypothesized that breast or ovarian cancer cells with mutant BRCA1 would exhibit selective sensitivity to elesclomol or treatment regimens containing elesclomol. First, we determined the effect of BRCA1 on the cellular response to oxidative stress and elesclomol using human ovarian cancer cells isogenic for BRCA1. Compared to mutant BRCA1 cells (UWB1.289), wild-type BRCA1 cells (UWB1.289+BRCA1) produced significantly greater levels of BRCA1 mRNA (p=0.009), expressed markedly higher levels of BRCA1 protein in the nucleus, and showed significantly greater sensitivity to hydrogen peroxide (p=0.002) as evidenced by RTqPCR, Western blot analysis, and MTT assay, respectively. Importantly, mutant BRCA1 cells displayed an approximate 100-fold greater sensitivity to elesclomol compared to wild-type BRCA1 cells as determined by MTT assay. These data suggest that the oxidative stress induced by elesclomol may be used to selectively target cancer cells with mutant BRCA1 due to their defective BER phenotype. We next asked whether elesclomol may be combined with other agents used clinically or experimentally for the treatment of BRCA1-mutated cancers, including standard chemotherapy drugs and PARP inhibitors. Elesclomol exhibited synergistic sensitivity when combined with DNA-damaging agents, including doxorubicin or cisplatin, in breast cancer cells with mutant BRCA1 (SUM149) as determined by combination index and isobologram analysis. On the other hand, a synergistic effect was not observed with the anti-microtubule agent paclitaxel, which is consistent with a phase III study that evaluated this combination for the treatment of advanced melanoma. However, elesclomol in combination with PARP inhibitors, including rucaparib or talazoparib, indeed showed synergism in breast cancer cells with mutant BRCA1. These data suggest that elesclomol may be used in combination with other anticancer agents to further exploit defects in DNA repair due to mutant BRCA1. In conclusion, elesclomol may be explored as a novel component of treatment regimens for targeting BRCA1-mutated breast and ovarian cancers. Citation Format: Maria Kammire, Emily Fannin, James M. Ford, Elizabeth Alli. Targeting BRCA1-mutated cancer cells with elesclomol [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4846.