Triple-negative breast cancer (TNBC) is the most aggressive and heterogeneous subtype of breast cancer, which lack therapeutic targets like estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Therefore, chemotherapy with antiproliferative agents like Docetaxel (DTX) remains the standard of care for TNBC patients. Unfortunately, many tumors acquire resistance to chemotherapy, accelerating metastasis and decreasing patient survival rates (1-3). This raises a need for the identification of new compounds that can be used to treat resistant tumors. Natural products (NPs) are a promising source of novel anticancer agents since their structural diversity and unique mechanisms of action can selectively exploit vulnerabilities in resistant TNBC cells (4-6). In this study, a high-throughput screening (HTS) campaign was conducted on the TNBC line HCC1806 resistant to docetaxel (RCCL collection, University of Kent) treated with 10,000 microbial extracts from MEDINA’s Library produced by geographically diverse fungi and actinomycetes. To improve translatability of the results, both two-dimensional (2D) and three-dimensional (3D) cell cultures in 384- well format were used to identify cytotoxicity by MTT and high content imaging respectively. As a result, 15 extracts were identified as active hits. The identification of these microbial natural product hits constitutes a critical first step toward the discovery and isolation of novel compounds capable of reversing docetaxel resistance in TNBC, thereby establishing a foundation for future mechanistic and preclinical investigations in this promising area of cancer therapeutics.
Poster
