Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):E9903-E9912. doi: 10.1073/pnas.1716009114. Epub 2017 Oct 30.
Expression of the transcription factor FOXC2 is induced and necessary for successful epithelial-mesenchymal transition, a developmental program that when activated in cancer endows cells with metastatic potential and the properties of stem cells. As such, identifying agents that inhibit the growth of FOXC2-transformed cells represents an attractive approach to inhibit chemotherapy resistance and metastatic dissemination. From a high throughput synthetic lethal screen, we identified a small molecule, FiVe1, which selectively and irreversibly inhibits the growth of mesenchymally transformed breast cancer cells and soft tissue sarcomas of diverse histological subtypes. FiVe1 targets the intermediate filament and mesenchymal marker vimentin (VIM) in a mode which promotes VIM disorganization and phosphorylation during metaphase, ultimately leading to mitotic catastrophe, multinucleation, and the loss of stemness. These findings illustrate a previously undescribed mechanism for interrupting faithful mitotic progression and may ultimately inform the design of therapies for a broad range of mesenchymal cancers.
转录因子 FOXC2 的表达被诱导并对上皮-间充质转化（EMT）是必要的，这是一种发育程序，当它在癌症中被激活时，赋予细胞转移潜能和干细胞特性。因此，鉴定能够抑制 FOXC2 转化细胞生长的药物代表了一种抑制化疗耐药性和转移扩散的有吸引力的方法。通过高通量合成致死筛选，我们鉴定出一种小分子化合物 FiVe1，它能够选择性和不可逆地抑制间充质转化的乳腺癌细胞和多种组织学亚型的软组织肉瘤的生长。FiVe1 以一种促进中期 VIM 解聚和磷酸化的方式靶向中间丝和间充质标志物波形蛋白（VIM），最终导致有丝分裂灾难、多核化和干性丧失。这些发现说明了一种以前未描述的中断忠实有丝分裂进程的机制，最终可能为广泛的间充质癌症的治疗设计提供信息。
