Abstract 2320: In vivo characterization of small molecule inhibitors of replication protein A: Implications for cancer therapy

Abstract

Abstract The nucleotide excision repair (NER) pathway catalyzes the removal of bulky DNA adducts from the genome and aids in maintaining genomic stability. The NER pathway has two subsets; global-genomic NER (GG-NER) and transcription coupled NER (TC-NER). They differ mainly in steps involving the recognition of the DNA lesion. The NER pathway plays a very important role in the recognition, removal and repair of intra-strand adducts induced by cisplatin; a commonly used chemotherapeutic agent. Previous studies have demonstrated that a decrease in NER activity enhances cancer sensitivity to cisplatin. The recognition of DNA damage involves a series of proteins including the xeroderma pigmentosum group A and C proteins (XPA and XPC) and Replication Protein A (RPA). RPA, a single-strand DNA binding protein, plays an essential role in both NER sub-pathways in addition to DNA replication. This makes RPA an ideal protein to target cancer therapy. Previous studies from our lab identified compounds which disrupt RPA's ssDNA binding activity in vitro. We sought to further characterize these RPA small molecule inhibitors (SMI) in cancer cell culture models. Using lung and ovarian cancer cell lines, viability curves, apoptosis assays, cell cycle analysis, signaling and transcription regulation were analyzed with single agent treatment and in combination with cisplatin. Results demonstrate potent cell killing in single agent studies and lengthening of the G1/ S-phase of the cell cycle. RPA SMIs also induce cell death through a classical apoptotic pathway. Additionally, data demonstrate a synergistic relationship with cisplatin with sequential treatment. Cell signaling analyses and DNA repair gene expression studies are ongoing to further determine the DNA damage response induced by these compounds. Overall these data demonstrate the therapeutic potential of SMI of RPA in treatment of cancer as single agents and in combination with cisplatin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2320. doi:10.1158/1538-7445.AM2011-2320