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STAT 3 activation confers trastuzumab‐emtansine (T‐ DM 1) resistance in HER 2‐positive breast cancer

2018; Wiley; Volume: 109; Issue: 10 Linguagem: Inglês

10.1111/cas.13761

1349-7006

Lei Wang, Quanren Wang, Mingzhao Gao, Fu Li, Yun Li, Haitian Quan, Liguang Lou,

Monoclonal and Polyclonal Antibodies Research

Trastuzumab‐emtansine (T‐ DM 1) is an antibody‐drug conjugate that has been approved for the treatment of human epidermal growth factor receptor 2 ( HER 2)‐positive metastatic breast cancer. Despite the remarkable efficacy of T‐ DM 1 in many patients, resistance to this therapeutic has emerged as a significant clinical problem. In the current study, we used BT ‐474/ KR cells, a T‐ DM 1‐resistant cell line established from HER 2‐positive BT ‐474 breast cancer cells, as a model to investigate mechanisms of T‐ DM 1 resistance and explore effective therapeutic regimens. We show here for the first time that activation of signal transducer and activator of transcription 3 ( STAT 3) mediated by leukemia inhibitory factor receptor (LIFR) overexpression confers resistance to T‐ DM 1. Moreover, secreted factors induced by activated STAT 3 in resistant cells limit the responsiveness of cells that were originally sensitive to T‐ DM 1. Importantly, STAT 3 inhibition sensitizes resistant cells to T‐ DM 1, both in vitro and in vivo, suggesting that the combination T‐ DM 1 with STAT 3‐targeted therapy is a potential treatment for T‐ DM 1‐refractory patients.