Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo

• Published in: Breast cancer research : BCR 2011-04, Vol.13 (2), p.R46-R46, Article R46
• Main Authors: Barok, Mark, Tanner, Minna, Köninki, Katri, Isola, Jorma
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized - pharmacology; Antibody-Dependent Cell Cytotoxicity - drug effects; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer cells; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm; Female; Growth; Humans; Immunohistochemistry; Maytansine - analogs & derivatives; Maytansine - pharmacology; Mice; Mice, SCID; Mitosis - drug effects; Quinazolines - pharmacology; Receptor, ErbB-2 - biosynthesis; Trastuzumab; Xenograft Model Antitumor Assays
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/bcr2868

Trastuzumab is widely used for the treatment of HER2-positive breast cancer. Despite encouraging clinical results, a significant fraction of patients are, or become, refractory to the drug. To overcome this, trastuzumab-DM1 (T-DM1), a newer, more potent drug has been introduced. We tested the efficacy and mechanisms of action of T-DM1 in nine HER2-positive breast cancer cell lines in vitro and in vivo. The nine cell lines studied included UACC-893, MDA-453 and JIMT-1, which are resistant to both trastuzumab and lapatinib. AlamarBlue cell-proliferation assay was used to determine the growth response of breast cancer cell lines to trastuzumab and T-DM1 in vitro. Trastuzumab- and T-DM1-mediated antibody-dependent cellular cytotoxicity (ADCC) was analysed by measuring the lactate dehydrogenase released from the cancer cells as a result of ADCC activity of peripheral blood mononuclear cells. Severe Combined Immunodeficient (SCID) mice were inoculated with trastuzumab-resistant JIMT-1 cells to investigate the tumour inhibitory effect of T-DM1 in vivo. The xenograft samples were investigated using histology and immunohistochemistry. T-DM1 was strongly growth inhibitory on all investigated HER2-positive breast cancer cell lines in vitro. T-DM1 also evoked antibody-dependent cellular cytotoxicity (ADCC) similar to that of trastuzumab. Outgrowth of JIMT-1 xenograft tumours in SCID mice was significantly inhibited by T-DM1. Histologically, the cellular response to T-DM1 consisted of apoptosis and mitotic catastrophe, the latter evidenced by an increased number of cells with aberrant mitotic figures and giant multinucleated cells. Our results suggest mitotic catastrophe as a previously undescribed mechanism of action of T-DM1. T-DM1 was found effective even on breast cancer cell lines with moderate HER2 expression levels and cross-resistance to trastuzumab and lapatinib (MDA-453 and JIMT-1).