The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

Peipei Liu,Dianwen Ju,Ziyu Wang,Ping Song,Yongping Li,Wenjing Zai,Jiajun Fan

doi:10.1186/s13568-020-01044-0

Abstract

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.

Highlights

Approximately 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 2015)
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 2020)
SK-BR-3 cells were more sensitive to T-DM1 than BT-474 cells, which was consistent with HER2 expression levels in these two cells as reported in previous studies (Lewis Phillips et al 2008; Takegawa et al 2019)

Summary

Introduction

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 2015). 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 2005; Slamon et al 2011). Liu et al AMB Expr (2020) 10:107 chemotherapy are found to have residual invasive breast cancer at surgery (Darini et al 2019; Zhang et al 2011). 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. It’s crucial to conduct in-depth investigation on the molecular mechanisms of T-DM1, which could provide novel strategies to optimize clinical outcomes

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Conclusion