Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment

• Published in: Scientific reports Vol. 14; no. 1; pp. 22487 - 15
• Main Authors: Koksalar Alkan, Fulya, Caglayan, Ahmet Burak, Alkan, Hilmi Kaan, Benson, Elayne, Gunduz, Yunus Emre, Sensoy, Ozge, Durdagi, Serdar, Zarbaliyev, Elbrus, Dyson, Greg, Assad, Hadeel, Shull, Austin, Chadli, Ahmed, Shi, Huidong, Ozturk, Gurkan, Korkaya, Hasan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 692/4028; Animals; Apoptosis; Breast cancer; Cell Line, Tumor; Clinical trials; Cyclophosphamide; Cyclophosphamide - pharmacology; Cyclophosphamide - therapeutic use; Cytotoxicity; Disease resistance; Diterpenes - pharmacology; Diterpenes - therapeutic use; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Female; Hsp70 protein; Humanities and Social Sciences; Humans; Immune system; Immunosuppressive agents; Lymphocytes T; Malignancy; Metastases; Mice; Mice, Inbred BALB C; multidisciplinary; Myc protein; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Organophosphates; Phenanthrenes - pharmacology; Phenanthrenes - therapeutic use; Science; Science (multidisciplinary); Stem cells; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triptolide; Tumor cell lines; Tumor cells; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-72989-6

Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.