No abstract

Early-onset gastric cancer demonstrates advanced stage of disease, and a high incidence of poorly-differentiated and signet-cell type carcinoma. Overall survival is poor with no added benefit to surgical intervention in advanced disease.

PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs raising important questions concerning long-term off-target effects. Here we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage dependent catalytic activation. Further, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anti-cancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Lastly, the development of a high-throughput (HT) PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors.