Abstract ES01-1: Targeting the DNA damage response in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) comprises approximately 25 percent of breast cancer deaths. There is a critical need to develop better therapeutic options for TNBC patients. We hypothesize that at least a subset of these cancers are especially dependent on DNA repair mechanisms that are coordinated by the ATR kinase-dependent DNA damage response signaling pathway. This hypothesis has been tested using genetic and chemical genetic approaches. We are working to develop small molecule inhibitors of the ATR pathway, understand how they work, and identify when these targeted therapies may provide clinical benefit. Our studies of an ATR selective inhibitor indicate that it kills cells due to a requirement for ATR signaling to complete DNA replication. ATR inhibition is synergistic with other chemotherapeutic agents such as platinum crosslinking drugs. ATR-inhibitor treated cells accumulate toxic DNA double-strand breaks and large stretches of single-stranded DNA through an active process catalyzed by deregulated nucleases and helicases. Effective biomarkers of ATR inhibition include DNA-PK, H2AX, RPA, and ATR phosphorylation. We have also worked with colleagues at Vanderbilt Medical School to identify additional therapeutic targets and develop small molecule inhibitors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES01-1.