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.

曲妥珠单抗（T-DM1）是曲妥珠单抗的抗体-药物共轭物（ADC）和细胞毒剂emtansine（DM1），已被批准用于曲妥珠单抗和紫杉烷的先后治疗转移性HER2阳性乳腺癌。T-DM1展现出令人印象深刻的功效，这促使人们需要对T-DM1细胞毒性的潜在机制进行进一步的研究。先前的研究表明自噬对于癌症治疗至关重要，但是尚未研究自噬在T-DM1治疗中的作用。在这里，我们首次证明T-DM1在HER2阳性SK-BR-3和BT-474乳腺癌细胞中触发了明显的自噬。使用药理抑制剂氯喹（CQ）或LY294002阻止自噬可部分减少T-DM1诱导的细胞凋亡和Caspase-3 / 7活化，提示自噬在HER2阳性乳腺癌细胞中由T-DM1诱导的细胞毒性中起重要作用。进一步的研究表明，Akt / mTOR信号通路以时间依赖的方式参与T-DM1诱导的自噬。总而言之，我们的结果突出了自噬作为T-DM1诱导的细胞毒性的新机制的重要作用，并阐明了T-DM1诱导的自噬与人HER2阳性乳腺癌细胞凋亡之间的关键关系，从而为自噬提供了新的见解。 T-DM1的潜在抗肿瘤机制。