Open AccessSTAT 3 activation confers trastuzumab‐emtansine (T‐ DM 1) resistance in HER 2‐positive breast cancer
Author(s) -
Wang Lei,
Wang Quanren,
Gao Mingzhao,
Fu Li,
Li Yun,
Quan Haitian,
Lou Liguang
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13761
Subject(s) - trastuzumab emtansine , trastuzumab , stat protein , cancer research , medicine , stat3 , metastatic breast cancer , breast cancer , leukemia inhibitory factor receptor , cancer , pharmacology , leukemia inhibitory factor , biology , cytokine , interleukin 6 , signal transduction , biochemistry
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.