A data driven approach to identify ZM-447439 as a potential repurposed drug to overcome tamoxifen-resistance in breast cancer

Abstract

Background: Tamoxifen is the most commonly used endocrine therapy (ET) for Breast Cancer (BC) patients expressing estrogen receptors (ER), representing almost 70% of all cases. However, one third of early stage BC patients demonstrate endocrine resistance to tamoxifen over the initial five-year treatment period, prompting significant research effort on identifying other drugs to alleviate tamoxifen resistance in ER + BC patients.Methods: We combined a total of 229 tamoxifen resistant and 363 tamoxifen sensitive tumors and tumor cell lines, to select genes that showed consistency as either up- or down- regulated differential expression among these datasets. We use these genes as the input to identify the drugs and compounds in Library of Integrated Network-Based Cellular Signatures (LINCS) database that can reverse the expression of these genes. With an innovative and comprehensive scoring system, we performed quality assessment on the results and prioritized drugs. Finally, we validated top five drugs using in vitro cell culture experiments.Results: We identified that ZM-447439, an aurora kinase inhibitor, can reverse the gene signatures associated with tamoxifen resistance. This was accomplished by a novel bioinformatics approach and scoring system, screening from over 20,000 small molecules in the Library of Integrated Network-Based Cellular Signatures (LINCS) database. The in vitro cell culture experiments showed that ZM-447439 had high potency to reverse gene expression in the tamoxifen-resistance BC cell line (MCF7-RR).Conclusion: We demonstrate the utility of a bioinformatics repurposing approach to identify candidate drug ZM-447439 with the potential to treat patients with acquired tamoxifen resistance.