Systems Pharmacology-Based Precision Therapy and Drug Combination Discovery for Breast Cancer.

Breast cancer (BC) is a common disease and one of the main causes of death in females worldwide. In the omics era, researchers have used various high-throughput sequencing technologies to accumulate massive amounts of biomedical data and reveal an increasing number of disease-related mutations/genes. It is a major challenge to use these data effectively to find drugs that may protect human health. In this study, we combined the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drugs that could be used to treat different BC subtypes. We used this strategy to screen four BC subtype-specific drug combinations and verified the potential activity of combining gefitinib and irinotecan in triple-negative breast cancer (TNBC) through in vivo and in vitro experiments. The results of cell and animal experiments demonstrated that the combination of gefitinib and irinotecan can significantly inhibit the growth of TNBC tumour cells. The results also demonstrated that this systems pharmacology-based precision drug discovery strategy effectively identified important disease-related genes in individuals and special groups, which supports its efficiency, high reliability, and practical application value in drug discovery.

Identification of NUDT5 Inhibitors From Approved Drugs.

Recent studies have revealed the important role of NUDT5 in estrogen signaling and breast cancer, but research on the corresponding targeted therapy has just started. Drug repositioning strategy can effectively reduce the time and economic resources spent on drug discovery. To find novel inhibitors of NUDT5, we investigated the previously identified connectivity map-based drug association models and found eighteen FDA approved drugs as candidates. The molecular docking and molecular dynamic simulation were performed and revealed that fourteen organic drugs have the potential to bind the NUDT5 target. Eight representative drugs were selected to perform the cell line viability inhibition analysis, and the results showed that seven of them were able to suppress MCF7 breast cancer cells. Two drugs, nomifensine and isoconazole, showed lower IC50 than the known antiestrogens raloxifene and tamoxifen, and they deserve further pharmacodynamic investigations to test their feasibility for use as NUDT5 inhibitors.