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- Title
Therapeutic activity of DCC‐2036, a novel tyrosine kinase inhibitor, against triple‐negative breast cancer patient‐derived xenografts by targeting AXL/MET.
- Authors
Shen, Yingying; Zhang, Wei; Liu, Jianghua; He, Jun; Cao, Renxian; Chen, Xiguang; Peng, Xiuda; Xu, Haifan; Zhao, Qiang; Zhong, Jing; Ding, Wenjun; Lei, Xiaoyong; Jiang, Yuyang; Zu, Xuyu
- Abstract
Triple‐negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor‐2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC‐2036 inhibited the proliferation, invasion, migration and epithelial‐mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC‐2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC‐2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC‐2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt‐NFκB signaling to exert its antitumor effect in TNBC. DCC‐2036 also inhibited the growth and metastasis of xenografted MDA‐MB‐231 cells (AXL/MET‐high TNBC cells) but not MDA‐MB‐468 cells (AXL‐low TNBC cells) in NSG mice in vivo. Furthermore, DCC‐2036 significantly inhibited tumor growth and invasion of AXL/MET‐high TNBC PDX tumors but not AXL/MET‐low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC‐2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC‐2036 even at a high dosage. Therefore, DCC‐2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression. What's new? Triple‐negative breast cancer (TNBC) is not sensitive to hormonal therapies or treatments targeted against HER2. Tyrosine kinases (TKs) could be potential targets due to their activation and high expression in multiple TNBC subtypes. This study shows that DCC‐2036, a third‐generation tyrosine kinase inhibitor with high selective activity for multiple TKs, has potent activity against TNBC. DCC‐2036 targets AXL/MET and regulates the downstream PI3K/Akt‐NFκB pathway in vitro and in vivo, without apparent toxicity. Moreover, DCC‐2036 exhibits more efficient anti‐proliferative activity than most clinical drugs. These data highlight DCC‐2036 as a promising targeting agent for treating TNBC, especially tumors that overexpress AXL/MET.
- Publication
International Journal of Cancer, 2019, Vol 144, Issue 3, p651
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.31915