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  3. Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer

Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer

  • Cell Death Discov. 2025 Sep 25;11(1):423. doi: 10.1038/s41420-025-02716-1.
Carmelo Cerra # 1,  Madeleine R C Tancock # 2,  Niko Thio 1 3,  Ada Koo 4,  AnnRann Wong 4,  Karla J Cowley 4,  Swati Varshney 5,  Madelynne O Willis 1,  Kaylene J Simpson 4 5 6,  Australian Ovarian Cancer Study Group,  David D L Bowtell 1 3,  Elaine Sanij 1 2 3 7 8,  Elizabeth L Christie 1 3,  Richard B Pearson 1 2 3,  Jian Kang 7 8,  Keefe T Chan 9 10
Affiliations

Affiliations

  • 1 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 2 Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • 3 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
  • 4 Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 5 Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Melbourne, VIC, Australia.
  • 6 Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, Australia.
  • 7 St. Vincent's Institute of Medical Research, Melbourne, VIC, Australia.
  • 8 Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC, Australia.
  • 9 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. keefe.chan@petermac.org.
  • 10 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia. keefe.chan@petermac.org.
  • # Contributed equally.
PMID: 40998801 DOI: 10.1038/s41420-025-02716-1
Abstract

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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