Abstract 1761: Breast cancers with compromised DNA repair exhibit selective sensitivity to elesclomol-induced oxidative DNA damage

Abstract

Abstract Hereditary breast cancers due to germline mutations in BRCA1 and sporadic breast cancers of the basal-like subtype are often triple-negative, i.e. lack expression of estrogen and progesterone receptors and lack overexpression/amplification of the HER2/neu oncogene. Given that the triple-negative status of these cancers renders them relatively insensitive to existing “targeted” therapy, improved treatment options are needed. We tested a panel of cell lines that represent the different molecular subtypes of breast cancer for sensitivity to elesclomol, an experimental therapeutic that produces elevated levels of oxidative DNA damage, using the MTT assay. We found that both BRCA1-mutated and basal-like breast cancer cell lines with defective base-excision DNA repair (BER) were markedly more sensitive to elesclomol than cell lines that represent the normal breast or other subtypes of breast cancer with proficient BER. We also assessed sensitivity to elesclomol in breast cancer cell lines that were stably transduced with shRNA to OGG1, a BER glycosylase required for the repair of the most common type of oxidative DNA damage. Two different cell lines with decreased levels of OGG1 (shOGG1A, 50% knock-down; shOGG1B, 20% knock-down) were more sensitive to elesclomol (IC50 = 0.04nM and 0.3nM, respectively) compared to two different isogenic control cell lines (IC50 = 2nM and 3nM, respectively). Taken together, these data suggest that compromised repair of oxidative DNA damage by BER represents a functional target for elesclomol. Overall, BRCA1-mutated and/or basal-like breast cancers may benefit from treatment regimens that include elesclomol. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1761. doi:1538-7445.AM2012-1761