T-DM1 exhibits superior efficacy than trastuzumab mono-treatment or trastuzumab combined with other chemotherapeutic agents (Chen et al. T-DM1 retains trastuzumab activity and it can deliver DM1 to HER2-positive cells efficiently. T-DM1 was approved for the therapy of HER2-overexpressed metastatic breast cancer in patients who have progressed despite previously receiving therapy of trastuzumab and taxane (Hunter et al. Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody–drug conjugate (ADC) which covalently binds trastuzumab with toxic agent emtansine (DM1), a potent microtubule inhibitor, by non-reducible thioether linker (Hurvitz et al. These limitations raise the necessity for achieving better understanding of biological mechanisms of these agents and developing better approaches for the treatment of HER2-overexpressed breast cancer.
#T dm1 mechanism of action plus
In spite of the improvements in outcomes of HER2-targeted therapy, approximately a quarter of patients who have received HER2-targeted therapy plus neoadjuvant chemotherapy are then found to have residual invasive breast cancer at surgery (Darini et al. Trastuzumab, a humanized monoclonal antibody which targets HER2 extracellular domain, has been approved since 1998 as the prior neoadjuvant treatment for HER2-overexpressed metastatic breast cancer (Romond et al. Altogether, our results highlighted the important role of autophagy as a novel mechanism for T-DM1-induced cytotoxicity and elucidated the critical relationships between T-DM1-induced autophagy and apoptosis in human HER2-positive breast cancer cells, which provides novel insight into the underlying anti-tumor mechanism of T-DM1.Īpproximately 20–30% patients with breast cancer are characterized with overexpressed human epidermal growth factor receptor 2 (HER2) which is closely related with short time of recurrence, high risk of metastases and poor overall patient survival (Loibl and Gianni 2017 Rimawi et al. Further investigation demonstrated that Akt/mTOR signaling pathway was involved in T-DM1-induced autophagy in a time-dependent manner. Blocking autophagy with pharmacological inhibitors chloroquine (CQ) or LY294002 partly reduced T-DM1-induced apoptosis and Caspase-3/7 activation, suggesting that autophagy played an essential role in the cytotoxicity induced by T-DM1 in HER2-positive breast cancer cells. Here, we demonstrated for the first time that T-DM1 triggered obvious autophagy in HER2-positive SK-BR-3 and BT-474 breast cancer cells. Previous research suggested that autophagy was crucial for cancer therapy, but the role of autophagy in T-DM1 treatment has not been investigated. The impressive efficacy exhibited by T-DM1 has heightened the need for more further studies on the underlying mechanisms of T-DM1 cytotoxicity.
Trastuzumab emtansine (T-DM1), an antibody–drug conjugate (ADC) of trastuzumab and cytotoxic agent emtansine (DM1), has been approved for the therapy of metastatic HER2-positive breast cancer after prior treatment of trastuzumab and taxane.