Disitamab vedotin in preclinical models of HER2-positive breast and gastric cancers resistant to trastuzumab emtansine and trastuzumab deruxtecan

  • Transl Oncol. 2025 Jan 20:53:102284. doi: 10.1016/j.tranon.2025.102284.
Negar Pourjamal  1 ,  Vadim Le Joncour  2 ,  György Vereb  3 ,  Cilla Honkamaki  1 ,  Jorma Isola  4 ,  Jeffrey V Leyton  5 ,  Pirjo Laakkonen  6 ,  Heikki Joensuu  7 ,  Mark Barok  8
Affiliations
  • 1. Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland.
  • 2. Neuroscience Center, Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, Helsinki, Finland.
  • 3. Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; HUN-REN-UD Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • 4. Laboratory of Cancer Biology, Medical Faculty, University of Tampere, Tampere, Finland.
  • 5. School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
  • 6. 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; ICAN Digital Precision Medicine Flagship Program, University of Helsinki, Helsinki, Finland.
  • 7. Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland; Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
  • 8. Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland. Electronic address: [email protected].
PMID: 39837059 DOI: 10.1016/j.tranon.2025.102284
Abstract

Background: Most HER2-positive breast or gastric cancers eventually become resistant to the approved anti-HER2 antibody-drug conjugates (ADC) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Disitamab vedotin (DV) is a novel anti-HER2 ADC that binds to a different epitope on HER2 compared to trastuzumab. We assessed the efficacy of DV in breast and gastric Cancer cell lines and xenografts, including tumor models resistant to T-DM1 and T-DXd. Additionally, we investigated whether combining two anti-HER2 ADCs could enhance the efficacy of the individual ADCs.

Methods: The efficacy of DV, T-DM1, and T-DXd, both as single agents and in combinations, was assessed using an AlamarBlue cell proliferation assay in HER2-positive breast and gastric Cancer cell lines, including those resistant to T-DM1 and T-DXd. The efficacy of DV was evaluated also in breast and gastric Cancer SCID mouse xenografts that had progressed on T-DM1 and/or T-DXd. ADC combinations were tested in breast and gastric Cancer xenografts.

Results: DV was effective in cell lines resistant to T-DM1 and/or T-DXd, and it inhibited the growth of breast and gastric Cancer xenografts that had progressed on T-DM1 and/or T-DXd. The combinations of DV plus T-DM1 and DV plus T-DXd showed greater efficacy than the corresponding single agents in both breast and gastric Cancer cell lines and xenografts.

Conclusions: DV was effective in treating breast and gastric Cancer xenograft tumors resistant to T-DM1 and/or T-DXd. The combination of DV with T-DM1 or T-DXd demonstrated promising activity.

Keywords
Antibody drug conjugate; Disitamab vedotin; Human epidermal growth factor receptor 2; Trastuzumab deruxtecan; Trastuzumab emtansine.
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