Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors
Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors
复制标题
使用小分子激酶抑制剂靶向 BRK 阳性乳腺癌。
DOI：
10.1158/0008-5472.can-16-1038
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发表时间：
2017-01-01
期刊：
影响因子：
11.2
通讯作者：
Deng, Xianming
中科院分区：
文献类型：
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作者：
Jiang, Jie;Gui, Fu;Deng, Xianming
大约80%的乳腺癌过表达蛋白酪氨酸激酶6，它在乳腺癌细胞的增殖、存活和迁移中起着不同的致癌作用。然而，BRK抑制剂作为可能的治疗工具还有待探索。在这项研究中，我们使用一种平行的以化合物为中心的方法来发现一类新的药物，如XMU-MP-2，作为有效和选择性的BRK抑制剂。XMU-MP-2显示靶向特异性地抑制BRK激酶活性，并干扰由该活性介导的信号通路，从而抑制BRK阳性乳腺癌细胞的增殖。在小鼠异种移植模型中，XMU-MP-2抑制由致癌基因BRK驱动的肿瘤的生长，包括BRK转化的BA/F3细胞和BRK阳性的乳腺癌细胞。值得注意的是，XMU-MP-2与HER2抑制剂或ER阻断剂在体外和体内都能很好地阻止乳腺癌细胞的增殖，我们的发现为乳腺癌靶向治疗BRK激酶的概念提供了临床前的证据。巨蟹座；77(1)；175-86。©2016 AACR。
Approximately 80% of breast cancers overexpress the kinase breast tumor kinase (BRK)/protein tyrosine kinase 6, which has various oncogenic roles in breast cancer cell proliferation, survival, and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we used a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast cancer cells. Notably, XMU-MP-2 cooperated strongly with HER2 inhibitor or ER blockade to block breast cancer cell proliferation in vitro and in vivo Overall, our findings offer a preclinical proof of concept for therapeutic targeting of the BRK kinase in breast cancer. Cancer Res; 77(1); 175-86. ©2016 AACR.