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
  • 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: [email protected].
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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