Description:
<jats:title>Abstract</jats:title>
<jats:p>Synthetic lethality describes an interdependent relationship between two genes, where the loss of either one alone can be compensated, while the simultaneous loss of both genes causes a non-viable phenotype. In recent years, first therapeutics based on this concept entered the clinic, most notably the PARP inhibitors for BRCA1/2-mutated cancers.</jats:p>
<jats:p>In the present study, we analyzed synthetic lethal interactions in yeast to identify new and potentially synergistic drug combinations for breast cancer therapy. We were able to confirm significantly enhanced cytotoxicity for predicted drug pairs in breast cancer cell lines in vitro.</jats:p>
<jats:p>First, a predictor built from publicly available yeast genetic interactions in the Data Repository of Yeast Genetic INteraction (DRYGIN) was used to predict potential synthetic lethal genetic interactions in human. Independently, a data set containing all pharmacological approaches, targeted or cytostatic, in breast cancer therapy was created. These drug combinations and their respective targets were then analyzed regarding their coverage of predicted synthetic lethal interactions. New drug combinations, previously unused in breast cancer therapy, were identified in silico by combining drugs already in use for breast cancer therapy (individually or in other combinations) in such a manner that their combination covers one or more potential synthetic lethal gene pairs. From this set of new drug combination and their synthetic lethal gene pairs we further pursued the predicted interdependencies between farnesyl diphosphate synthase (FDPS) and tubulin, beta 1 (TUBB1) and between FDPS and phosphoinositide-dependent kinase-1 (PDPK1) as well as prostaglandin-endoperoxide synthase 2 (PTGS2). Drugs targeting these genes are celecoxib (PDPK1, PTGS2), an anti-inflammatory drug, and zoledronic acid (FDPS), a bone degradation inhibitor, as well as the cytotoxic agent paclitaxel (TUBB1).</jats:p>
<jats:p>We performed cell viability and cytotoxicity assays to determine therapeutic effects of celecoxib, zoledronic acid and paclitaxel alone and in combination on selected breast cancer cell lines.</jats:p>
<jats:p>Our results showed statistically significant decreases in cell viability for the combinational treatment with zoledronic acid and paclitaxel as well as with the per se non-cytotoxic combination of zoledronic acid and celecoxib when compared to single agent treatment.</jats:p>
<jats:p>In conclusion, we present a bioinformatics approach to predict potentially synergistic gene interactions based on synthetic lethality found in yeast and a strategy for utilizing these interactions for identifying new potentially synergistic drug combinations.</jats:p>
<jats:p>Citation Format: Michael Schwarz, Erwin Tomasich, Maximilian Marhold, Andreas Heinzel, Paul Perco, Peter Horak, Bernd Mayer, Michael Krainer. Drug combinations for breast cancer based on synthetic lethality screens in yeast. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2697.</jats:p>