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

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dc.contributor.authorKöksalar Alkan, Fulya
dc.contributor.authorÇağlayan, Ahmet Burak
dc.contributor.authorAlkan, Hilmi Kaan
dc.contributor.authorGündüz, Yunus Emre
dc.contributor.authorŞensoy, Özge
dc.contributor.authorÖztürk, Gürkan
dc.contributor.authorKorkaya, Hasan
dc.date.accessioned2025-08-27T11:09:53Z
dc.date.available2025-08-27T11:09:53Z
dc.date.issued2024
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Fizyoloji Ana Bilim Dalı
dc.description.abstractTriple 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.
dc.description.sponsorshipUnited States Department of Health & Human Services ; National Institutes of Health (NIH) - USA ; Office of the Administrator (NIH)
dc.identifier.citationKöksalar Alkan, F., Çağlayan, A. B., Alkan, H. K., Gündüz, Y. E., Şensoy, Ö., Öztürk, G. ... Korkaya, H. (2024). Dual activity of minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment. Scientific Reports, 14(1). http://dx.doi.org/10.1038/s41598-024-72989-6
dc.identifier.doi10.1038/s41598-024-72989-6
dc.identifier.issn2045-2322
dc.identifier.issue1
dc.identifier.pmid39341857
dc.identifier.scopus2-s2.0-85205237998
dc.identifier.scopusqualityQ1
dc.identifier.urihttp://dx.doi.org/10.1038/s41598-024-72989-6
dc.identifier.urihttps://hdl.handle.net/20.500.12511/13032
dc.identifier.volume14
dc.identifier.wosWOS:001325241700119
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorGündüz, Yunus Emre
dc.institutionauthorŞensoy, Özge
dc.institutionauthorÖztürk, Gürkan
dc.institutionauthorid0000-0001-5950-3436
dc.institutionauthorid0000-0003-0352-1947
dc.language.isoen
dc.relation.ecinfo:eu-repo/grantAgreement/EC/FP7/P30CA22453
dc.relation.ecinfo:eu-repo/grantAgreement/EC/FP7/R50CA251068-01
dc.relation.ecinfo:eu-repo/grantAgreement/EC/FP7/R01CA251676
dc.relation.ispartofScientific Reports
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectTriple Negative Breast Cancer
dc.subjectTNBC
dc.subjectTumor Microenvironment
dc.subjectTME
dc.subjectCancer Stem Cells
dc.titleDual activity of minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment
dc.typeArticle

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