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

Clin Exp Metastasis. 2024 Apr;41(2):91-102. doi: 10.1007/s10585-024-10278-2. Epub 2024 Feb 17.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ado-Trastuzumab Emtansine / pharmacology
  • Ado-Trastuzumab Emtansine / therapeutic use
  • Animals
  • Antibodies, Monoclonal*
  • Antineoplastic Agents* / therapeutic use
  • Breast Neoplasms* / pathology
  • Camptothecin* / analogs & derivatives
  • Female
  • Humans
  • Immunoconjugates* / pharmacology
  • Lung Neoplasms* / drug therapy
  • Mice
  • Mice, SCID
  • Oligopeptides*
  • Receptor, ErbB-2 / metabolism
  • Trastuzumab


  • Ado-Trastuzumab Emtansine
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Camptothecin
  • disitamab vedotin
  • Immunoconjugates
  • Oligopeptides
  • Receptor, ErbB-2
  • Trastuzumab
  • trastuzumab deruxtecan