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  3. Drug-tolerant persisting polyploid giant cancer cells mediate resistance to HER2-targeting antibody-drug conjugates

Drug-tolerant persisting polyploid giant cancer cells mediate resistance to HER2-targeting antibody-drug conjugates

  • Cancer Lett. 2025 Oct 10:630:217900. doi: 10.1016/j.canlet.2025.217900.
Narjes Yazdi 1,  Negar Pourjamal 1,  Riku Katainen 2,  Juho Väänänen 3,  Jun Dai 4,  Anna Vähärautio 5,  Jorma Isola 6,  Minna Kempas 1,  Vadim Le Joncour 7,  Pirjo Laakkonen 8,  Heikki Joensuu 9,  Mark Barok 10
Affiliations

Affiliations

  • 1 Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, University of Helsinki, Helsinki, Finland.
  • 2 Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship Program, University of Helsinki, Helsinki, Finland; Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 3 Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 4 Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 5 Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Foundation for the Finnish Cancer Institute, Helsinki, Finland.
  • 6 Laboratory of Cancer Biology, Medical Faculty, University of Tampere, Tampere, Finland.
  • 7 iCAN Digital Precision Cancer Medicine Flagship Program, University of Helsinki, Helsinki, Finland; Neuroscience Center, Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, Helsinki, Finland.
  • 8 iCAN Digital Precision Cancer Medicine Flagship Program, University of Helsinki, Helsinki, Finland; Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory Animal Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
  • 9 Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, University of Helsinki, Helsinki, Finland; Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
  • 10 Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, University of Helsinki, Helsinki, Finland. Electronic address: mark.barok@helsinki.fi.
PMID: 40614854 DOI: 10.1016/j.canlet.2025.217900
Abstract

Polyploid giant Cancer cells (PGCCs) contribute to resistance against various Cancer therapies. This study investigates whether HER2-directed antibody-drug conjugates (ADC) induce PGCCs and their role in drug resistance. HER2-positive breast Cancer (JIMT-1) and gastric Cancer (MKN7, SNU-216) cells were treated with HER2-directed ADCs, trastuzumab emtansine, trastuzumab deruxtecan, XMT-1522, and disitamab vedotin (DV). The induced persister cells were characterized using live cell imaging, confocal microscopy, immunohistochemistry, flow cytometry, gene expression analysis, SNP genotyping, and next-generation Sequencing. Drug sensitivity was assessed using the AlamarBlue assay and SCID mouse xenografts. All 4 ADCs induced PGCCs, with XMT-1522 and DV being the most effective. The induced giant cells were drug-resistant and exhibited drug-tolerant persister cell characteristics. HER2 protein levels were downregulated in persisting drug-tolerant PGCCs and their daughter cells. JIMT-1 cells lost HER2 amplification following XMT-1522 treatment, along with the loss of extrachromosomal DNA containing HER2. However, XMT-1522-treated MKN7 and SNU-216 cells, and DV-treated JIMT-1 cells, retained the amplicon. Drug-tolerant PGCCs upregulated Nectin-4, and treatment with enfortumab vedotin, a nectin-4-targeted ADC, inhibited the regrowth of JIMT-1 xenografts. ADC treatment induces PGCCs that contribute to drug resistance. ADC-induced drug-tolerant PGCCs express Nectin-4, which may serve as a potential therapeutic target.

Keywords

Antibody drug conjugate; Disitamab vedotin; Extrachromosomal DNA; Human epithelial growth factor receptor-2; Nectin-4; Polyploid giant cancer cells; XMT-1522.

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