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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.

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