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. The impressive efficacy exhibited by T-DM1 has heightened the need for more further studies on the underlying mechanisms of T-DM1 cytotoxicity. Previous research suggested that autophagy was crucial for
cancer therapy, but the role of autophagy in T-DM1 treatment has not been investigated. 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. 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. Further investigation demonstrated that Akt/mTOR signaling pathway was involved in T-DM1-induced autophagy in a time-dependent manner. 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.