Abstract
Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugated to the microtubule-targeting agent emtansine (DM1). T-DM1 is an effective agent in the treatment of patients with HER2-positive breast cancer whose disease has progressed on the first-line trastuzumab containing chemotherapy. However, both primary and acquired tumour resistance limit its efficacy. Increased levels of the phosphorylated form of Translationally Controlled Tumour Protein (phospho-TCTP) have been shown to be associated with a poor clinical response to trastuzumab therapy in HER2-positive breast cancer. Here we show that phospho-TCTP is essential for correct mitosis in human mammary epithelial cells. Reduction of phospho-TCTP levels by dihydroartemisinin (DHA) causes mitotic aberration and increases microtubule density in the trastuzumab-resistant breast cancer cells HCC1954 and HCC1569. Combinatorial studies show that T-DM1 when combined with DHA is more effective in killing breast cells compared to the effect induced by any single agent. In an orthotopic breast cancer xenograft model (HCC1954), the growth of the tumour cells resumes after having achieved a complete response to T-DM1 treatment. Conversely, DHA and T-DM1 treatment induces a severe and irreversible cytotoxic effect, even after treatment interruption, thus, improving the long-term efficacy of T-DM1. These results suggest that DHA increases the effect of T-DM1 as poison for microtubules and supports the clinical development of the combination of DHA and T-DM1 for the treatment of aggressive HER2-overexpressing breast cancer.
Highlights
HER2-positive breast cancer (HER2+ BC), which represents about 25–30% of breast cancers, is characterized by the overexpression of the human epidermal growth factor receptor 2 (HER2/neu), a tyrosine kinase receptor (RTK)
We have previously shown in HER2 overexpressing breast cancer cell lines that DHA, by reducing the expression levels of the phosphorylated form of TCTP, enhances the response to treatment with drugs as doxorubicin, cisplatin and trastuzumab
We investigated the effect of DHA on HER2+ breast cancer cells resistant to trastuzumab
Summary
HER2-positive breast cancer (HER2+ BC), which represents about 25–30% of breast cancers, is characterized by the overexpression of the human epidermal growth factor receptor 2 (HER2/neu), a tyrosine kinase receptor (RTK). Therapies with monoclonal antibodies of high affinity specific for the HER2 receptor, or combinations of multiple anti-HER2 antibodies, have led to a significant improvement in therapeutic response; despite this, many patients develop resistance to therapy [1,2,3]. T-DM1 treatment provides significant clinical benefit in breast cancer patients previously treated with chemotherapy and HER2-directed therapy, and in patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy [4,5,6,7]. Identification of novel combination therapies for T-DM1 represents a major challenge to improve treatment effectiveness and to delay or prevent acquired resistance to HER2 inhibition
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