2. Academic Validation
  3. Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model

Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model

  • Clin Exp Metastasis. 2024 Feb 17. doi: 10.1007/s10585-024-10278-2.
Negar Pourjamal 1 2,  Narjes Yazdi 1 2,  Aleksi Halme 3,  Vadim Le Joncour 3,  Pirjo Laakkonen 3 4 5,  Pipsa Saharinen 3 6,  Heikki Joensuu 1 2 7,  Mark Barok 8 9 10
Affiliations

Affiliations

  • 1 Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
  • 2 Laboratory of Molecular Oncology, University of Helsinki, Helsinki, Finland.
  • 3 Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 4 Neuroscience Center, Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, Helsinki, Finland.
  • 5 Laboratory Animal Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
  • 6 Wihuri Research Institute, University of Helsinki, Helsinki, Finland.
  • 7 Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
  • 8 Helsinki University Hospital and University of Helsinki, Helsinki, Finland. mark.barok@helsinki.fi.
  • 9 Laboratory of Molecular Oncology, University of Helsinki, Helsinki, Finland. mark.barok@helsinki.fi.
  • 10 Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, 00290, Finland. mark.barok@helsinki.fi.
PMID: 38367127 DOI: 10.1007/s10585-024-10278-2
Abstract

Human epidermal growth factor 2 (HER2)-positive breast Cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast Cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast Cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast Cancer.

Keywords

Antibody drug conjugate; Breast cancer; Disitamab vedotin; Human epidermal growth factor receptor 2; Lung metastasis; Trastuzumab deruxtecan; Trastuzumab emtansine.

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