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

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.

Fig. 1

Establishment of a novel HER2-positive breast cancer lung metastasis model. The L-JIMT-1 cell line was established from a lung metastasis of a SCID mouse injected intravenously with the JIMT-1 cells. When the L-JIMT-1 cells were injected intravenously into mice, more lung metastases developed within a shorter time compared to the JIMT-1 injected mice

Fig. 2

Flow cytometric quantification of cell surface EGFR, HER2, and HER3 expression on JIMT-1 and L-JIMT-1 cells. **p < 0.01, ***p < 0.001

Fig. 3

Growth inhibition of anti-EGFR and/or anti-HER2 tyrosine kinase inhibitors on JIMT-1 and L-JIMT-1 cells, and on MCF-7 (negative control) and SKBR-3 (positive control) cells (A-E). **p < 0.01, ***p < 0.001

Fig. 4

Growth inhibition of anti-HER2 antibody-drug conjugates on JIMT-1 and L-JIMT-1 cells, and on MCF-7 (negative control) and SKBR-3 (positive control) cells (A-C). **p < 0.01, ***p < 0.001

Fig. 5

The effect of T-DM1, T-DXd, and DV on the growth of HER2-positive breast cancer lung metastases in SCID mice. A, Tumor and vasculature volumes (TVV) were assessed with bi-weekly micro-CT imaging. The mice received the treatment on week 8 (arrow). B, Survival of the mice. C, Number of lung metastases counted on subserial sections of the lungs. D, Largest diameter of lung metastases measured on subserial sections of the lungs. *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 6

Representative micro-CT images of mice injected with L-JIMT-1 cells intravenously and then treated with PBS (A-B), T-DM1 (C-D), T-DXd (E-F), or DV (G-H) 8 weeks after the injection. Micro-CT images were taken on week 7 (before treatment) and at the end of the study (PBS treatment, week 11; ADC treatments, week 15). The yellow arrows in panels B, D, F, and H point at lung metastases at the end of the study