Abstract 3442: Olaparib increases antitumor effects on epigenetically RAD51C-deficient human cancer cells.

Abstract

Abstract Background: The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has been found to have a therapeutic potential for treating cancers that have an impaired DNA repair ability. RAD51C has been reported to play an essential role in DNA repair mediated by homologous recombination. In addition, RAD51C is a gene that affects human cancer susceptibility, similar to BRCA1 and BRCA2. RAD51C-defective cancers can therefore be potentially treated with olaparib because DNA damage induced by olaparib cannot be effectively repaired by HR since RAD51C deficiency interferes with RAD51-mediated HR. Materials and Methods: We studied the growth inhibitory effects of olaparib on human cancer cell lines using clonogenic survival assays. Cell cycle analysis and molecular changed induced by olaparib were also performed. DNA methylation status in cancer cells and tumor tissue samples was also determined by using bisulfate sequencing. Results: Olaparib is effective to RAD51C-defective cells. Olaparib leads to the accumulation of unrepaired DSBs due to dysfunctional RAD51 foci formation along with increased caspase 3-dependent cell death and G2/M arrest in RAD51C-defective cells. Moreover, the growth of RAD51C-deficient SNU601 tumor cells in a xenograft model decreased significantly following treatment with olaparib. Furthermore, RAD51C expression was significantly decreased in cancer and the lack of RAD51C was attributed to DNA methylation and histone modification. Our findings showed that the loss of RAD51C expression due to epigenetic silencing leads to olaparib sensitivity in cancer cells. Conclusion: The loss of RAD51C expression was frequently associated with human cancers. We used a novel synthetic lethal approach using PARP inhibitors and observed that RAD51C was a participant in the DNA repair pathway. Our findings have potential clinical application for treating cancers with RAD51C deficiencies. Furthermore, we determined that RAD51C may serve as a novel biomarker for identifying olaparib-sensitive patients, thereby allowing physicians to select the most effective modalities for treating these individuals. Citation Format: Ahrum Min, Seongyeong Kim, Seock-Ah Im, Young-Kwang Yoon, Sang-Hyun Song, Hyun-Jin Nam, Hyung-Seok Hur, Kyung-Hun Lee, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Mark J. O`Connor, Woo-Ho Kim, Yung-Jue Bang. Olaparib increases antitumor effects on epigenetically RAD51C-deficient human cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3442. doi:10.1158/1538-7445.AM2013-3442