Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer
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Le résumé fourni par la source
Treatments for high-grade serous ovarian cancer (HGSOC) are initially effective but most invariably fail. Although they can successfully suppress the bulk of the tumour cell population, residual cancer cells can enter alternative therapy-resistant cell fates highlighted by proliferative arrest. Understanding the nature of these fates and how cells may resume uncontrolled proliferation will lead to the development of new treatments for HGSOC. In this study, we examine the response of HGSOC cells to standard of care cisplatin chemotherapy and to the RNA Polymerase I transcription inhibitor CX-5461/Pidnarulex, two drugs that elicit a potent DNA damage response and growth arrest. Here, we identify that HGSOC cells exposed to these therapies show multiple hallmarks of therapy-induced senescence (TIS) and derive a core TIS gene expression signature irrespective of genetic background or senescence trigger. Given that TIS is a potentially escapable state, we have performed a focussed drug screen to identify drugs that eradicate senescent HGSOC cells. We identify that therapy-induced senescent HGSOC cells, including those with decreased sensitivity to senolytic drugs that inhibit the pro-survival protein BCL-XL, can be eliminated using drugs that induce ferroptosis, an iron-dependent form of cell death. Mechanistically, we demonstrate that senescent HGSOC cells have altered expression of regulators of iron metabolism leading to intracellular iron overload that underpins this targetable vulnerability. Together, we highlight elevated levels of iron as a TIS biomarker in HGSOC and the potential of inducing ferroptosis to eradicate residual HGSOC cells following initial therapy.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer
- Date Crossref
- 25/09/2025
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Peter MacCallum Cancer Centre pays non établi dans la noticeÉtablissement de santé
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Australian Regenerative Medicine Institute pays non établi dans la noticeStructure de recherche
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Monash University Department of Biochemistry and Molecular Biology pays non établi dans la noticeUniversité ou école supérieure
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The University of Melbourne Sir Peter MacCallum Department of Oncology pays non établi dans la noticeUniversité ou école supérieure
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Victorian Centre for Functional Genomics pays non établi dans la noticeUniversité ou école supérieure
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St Vincent's Hospital Melbourne pays non établi dans la noticeÉtablissement de santé
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St Vincents Institute of Medical Research pays non établi dans la noticeOrganisation à but non lucratif
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St. Vincent's Institute of Medical Research pays non établi dans la noticeStructure de recherche
Peter MacCallum Cancer Centre, Australian Regenerative Medicine Institute et Department of Biochemistry and Molecular Biology — Monash University, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.