Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor, against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET
Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor, against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET
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DCC-2036（一种新型酪氨酸激酶抑制剂）通过靶向 AXL/MET 对三阴性乳腺癌患者来源的异种移植物的治疗活性
DOI：
10.1002/ijc.31915
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发表时间：
2019-02-01
影响因子：
6.4
通讯作者：
Zu，Xuyu
中科院分区：
文献类型：
--
作者：
Shen，Yingying;Zhang，Wei;Zu，Xuyu
三阴性乳腺癌（TNBC）对内分泌治疗和人表皮生长因子受体-2（HER 2）、雌激素受体（ER）和孕激素受体（PR）的靶向治疗不敏感。迫切需要TNBC的新靶标和新靶向治疗药物。我们的研究证实，DCC-2036抑制TNBC细胞的增殖、侵袭、迁移和上皮-间质转化（EMT），并诱导凋亡。此外，DCC-2036的抗增殖活性比大多数临床药物更有效。此外，DCC-2036与顺铂或拉帕替尼的组合对TNBC细胞具有协同作用。DCC-2036通过靶向AXL/MET，尤其是AXL，调节下游PI 3 K/Akt-NF κB信号通路发挥其抗肿瘤作用。DCC-2036还在体内抑制NSG小鼠中异种移植的MDA-MB-231细胞（AXL/MET-高TNBC细胞）的生长和转移，但不抑制MDA-MB-468细胞（AXL-低TNBC细胞）。此外，DCC-2036显著抑制AXL/MET-高TNBC PDX肿瘤的肿瘤生长和侵袭，但不抑制AXL/MET-低TNBC PDX肿瘤。这些结果强调了AXL/MET在癌症生长和转移中的作用，并进一步证实了DCC-2036的关键靶点是AXL和MET，尤其是AXL。此外，即使在高剂量下，DCC-2036也没有显著的毒性。因此，DCC-2036可能是治疗TNBC的潜在化合物，特别是对于AXL/MET过表达的肿瘤。
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 micein 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.