High-Throughput Tyrosine Kinase Activity Profiling Identifies FAK as a Candidate Therapeutic Target in Ewing Sarcoma
High-Throughput Tyrosine Kinase Activity Profiling Identifies FAK as a Candidate Therapeutic Target in Ewing Sarcoma
复制标题
DOI：
10.1158/0008-5472.can-12-1944
复制
发表时间：
2013-05-01
期刊：
影响因子：
11.2
通讯作者：
Stegmaier, Kimberly
中科院分区：
文献类型：
--
作者：
Crompton, Brian D.;Carlton, Anne L.;Stegmaier, Kimberly
尽管在过去十年中癌症发现的步伐加快，但在晚期儿科实体瘤的治疗方面取得的进展有限。酪氨酸激酶抑制是治疗人类恶性肿瘤的一种易处理的治疗方式。然而，对许多儿童实体瘤（如尤文肉瘤）的发展或维持至关重要的激酶知之甚少。使用荧光，珠为基础的技术来配置文件激活酪氨酸激酶，我们确定了粘着斑激酶（FAK，PTK 2）作为尤文肉瘤的候选目标。FAK是一种对细胞粘附、生长和存活至关重要的酪氨酸激酶。因此，它是基于癌症的治疗的一个引人注目的目标。在这项研究中，我们已经表明，FAK是高度磷酸化的原发性尤文肉瘤肿瘤样品和FAK的下调短发夹RNA和治疗FAK选择性激酶抑制剂，PF-562271，损害尤文肉瘤细胞系的生长和集落形成。此外，用PF-562271处理尤文肉瘤细胞系可诱导细胞凋亡，并导致AKT/mTOR和CAS活性下调。最后，我们表明FAK的小分子抑制剂在体内减弱了尤文肉瘤的生长。FAK抑制剂目前正处于成人恶性肿瘤的早期临床试验中，这些发现可能与尤文肉瘤患者直接相关。(C)2013年AACR。
Limited progress has been made in the treatment of advanced-stage pediatric solid tumors despite the accelerated pace of cancer discovery over the last decade. Tyrosine kinase inhibition is one tractable therapeutic modality for treating human malignancy. However, little is known about the kinases critical to the development or maintenance of many pediatric solid tumors such as Ewing sarcoma. Using a fluorescent, bead-based technology to profile activated tyrosine kinases, we identified focal adhesion kinase (FAK, PTK2) as a candidate target in Ewing sarcoma. FAK is a tyrosine kinase critical for cellular adhesion, growth, and survival. As such, it is a compelling target for cancer-based therapy. In this study, we have shown that FAK is highly phosphorylated in primary Ewing sarcoma tumor samples and that downregulation of FAK by short hairpin RNA and treatment with a FAK-selective kinase inhibitor, PF-562271, impaired growth and colony formation in Ewing sarcoma cell lines. Moreover, treatment of Ewing sarcoma cell lines with PF-562271 induced apoptosis and led to downregulation of AKT/mTOR and CAS activity. Finally, we showed that small-molecule inhibition of FAK attenuated Ewing sarcoma tumor growth in vivo. With FAK inhibitors currently in early-phase clinical trials for adult malignancies, these findings may bear immediate relevance to patients with Ewing sarcoma. (C) 2013 AACR.