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Peer-reviewedCC BY 4.0Molecular Oncology

Overcoming platinum resistance by the disulfiram metabolite CuET in novel preclinical models of human carcinomas

  • Stefanos Arampatzis1
  • Tereza Buchtová1
  • Jirina Bartkova1,2
  • Marie Lund Bay3
  • Christoffer Lynge Halvorsen1
  • Zuzana Machacova1
  • Zdenek Skrott4
  • Martin Mistrik4
  • Ekaterina Dulina1
  • Miguel Andujar‐Sanchez5
  • Estrid Høgdall6
  • Tine Henrichsen Schnack7
9 more authors
  • Claus Høgdall7,8
  • Berit Jul Mosgaard7
  • Marie Boennelycke9
  • Jacob Brink Laursen7
  • Allan Jensen10
  • Susanne K. Kjær7,8,10
  • Tuula Kallunki3,11
  • Robert Strauss1
  • Jiri Bartek1,2,12
12 affiliations
  1. 1Genome Integrity Group Danish Cancer Institute, Danish Cancer Society Copenhagen Denmark
  2. 2Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory Karolinska Institute Stockholm Sweden
  3. 3Cancer Invasion and Resistance Group Danish Cancer Institute, Danish Cancer Society Copenhagen Denmark
  4. 4Faculty of Medicine and Dentistry Institute of Molecular and Translational Medicine, Palacky University Olomouc Czech Republic
  5. 5Department of Pathology Complejo Hospitalario Universitario Insular Las Palmas Gran Canaria Spain
  6. 6Molecular Unit, Department of Pathology Copenhagen University Hospital, Herlev and Gentofte Hospital Denmark
  7. 7Department of Gynaecology Copenhagen University Hospital Rigshospitalet Denmark
  8. 8Department of Clinical Medicine University of Copenhagen Denmark
  9. 9Department of Pathology Copenhagen University Hospital Rigshospitalet Denmark
  10. 10Virus, Lifestyle and Genes Group Danish Cancer Institute, Danish Cancer Society Copenhagen Denmark
  11. 11Translational and Clinical Pharmacology, Department of Drug Design and Pharmacology University of Copenhagen Denmark
  12. 12Division of Cancer Research, Ninewells Hospital and Medical School University of Dundee UK
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Abstract

Overcoming resistance to standard‐of‐care chemotherapy represents an unmet need in oncology. To help address this challenge, here we established and characterized a panel of human cisplatin‐resistant lung and breast cancer cell lines and patient‐derived organoids from high‐grade serous ovarian carcinomas (HGSOC), and show that platinum resistance can be overcome by treatment with diethyldithiocarbamate‐copper (CuET), a metabolite of the alcohol‐aversion drug disulfiram. All platinum‐resistant models remained sensitive to CuET, consistent with distinct cytotoxicity mechanisms: proteotoxic stress for CuET and DNA damage for cisplatin, respectively. Platinum adduct and DNA damage response analyses suggested diverse mechanisms of cisplatin resistance among our models. Considering potential CuET‐based therapies, our gene knock‐down and functional assays in preclinical models, complemented with immunohistochemical analysis of tissue samples from cohorts of triple‐negative breast cancer and HGSOC patients indicate that levels of metallothioneins, rather than NPL4 (the molecular target of CuET) warrant further evaluation as candidate biomarkers of CuET sensitivity. This dataset provides a resource of platinum‐resistant models of common carcinomas, identifies CuET as a compound overcoming such resistance and provides leads for predictive biomarker discovery, with potential clinical implications in oncology.

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Cite

BibTeXRIS
BibTeX
@article{arampatzis2026overcoming,
  title = {{Overcoming platinum resistance by the disulfiram metabolite CuET in novel preclinical models of human carcinomas}},
  author = {Stefanos Arampatzis and Tereza Buchtová and Jirina Bartkova and Marie Lund Bay and Christoffer Lynge Halvorsen and Zuzana Machacova and Zdenek Skrott and Martin Mistrik and Ekaterina Dulina and Miguel Andujar‐Sanchez and Estrid Høgdall and Tine Henrichsen Schnack and Claus Høgdall and Berit Jul Mosgaard and Marie Boennelycke and Jacob Brink Laursen and Allan Jensen and Susanne K. Kjær and Tuula Kallunki and Robert Strauss and Jiri Bartek},
  journal = {Molecular Oncology},
  year = {2026},
  month = nov,
  doi = {10.1002/1878-0261.70356},
  url = {https://doi.org/10.1002/1878-0261.70356},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Overcoming platinum resistance by the disulfiram metabolite CuET in novel preclinical models of human carcinomas
AU  - Stefanos Arampatzis
AU  - Tereza Buchtová
AU  - Jirina Bartkova
AU  - Marie Lund Bay
AU  - Christoffer Lynge Halvorsen
AU  - Zuzana Machacova
AU  - Zdenek Skrott
AU  - Martin Mistrik
AU  - Ekaterina Dulina
AU  - Miguel Andujar‐Sanchez
AU  - Estrid Høgdall
AU  - Tine Henrichsen Schnack
AU  - Claus Høgdall
AU  - Berit Jul Mosgaard
AU  - Marie Boennelycke
AU  - Jacob Brink Laursen
AU  - Allan Jensen
AU  - Susanne K. Kjær
AU  - Tuula Kallunki
AU  - Robert Strauss
AU  - Jiri Bartek
PY  - 2026
DA  - 2026/11/04
JO  - Molecular Oncology
DO  - 10.1002/1878-0261.70356
UR  - https://doi.org/10.1002/1878-0261.70356
AB  - Overcoming resistance to standard‐of‐care chemotherapy represents an unmet need in oncology. To help address this challenge, here we established and characterized a panel of human cisplatin‐resistant lung and breast cancer cell lines and patient‐derived organoids from high‐grade serous ovarian carcinomas (HGSOC), and show that platinum resistance can be overcome by treatment with diethyldithiocarbamate‐copper (CuET), a metabolite of the alcohol‐aversion drug disulfiram. All platinum‐resistant models remained sensitive to CuET, consistent with distinct cytotoxicity mechanisms: proteotoxic stress for CuET and DNA damage for cisplatin, respectively. Platinum adduct and DNA damage response analyses suggested diverse mechanisms of cisplatin resistance among our models. Considering potential CuET‐based therapies, our gene knock‐down and functional assays in preclinical models, complemented with immunohistochemical analysis of tissue samples from cohorts of triple‐negative breast cancer and HGSOC patients indicate that levels of metallothioneins, rather than NPL4 (the molecular target of CuET) warrant further evaluation as candidate biomarkers of CuET sensitivity. This dataset provides a resource of platinum‐resistant models of common carcinomas, identifies CuET as a compound overcoming such resistance and provides leads for predictive biomarker discovery, with potential clinical implications in oncology.
SN  - 1574-7891
SN  - 1878-0261
ER  -