Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston, MA 02215, USA.
Cancer Res. 2013 May 1;73(9):2873-83. doi: 10.1158/0008-5472.CAN-12-1944. Epub 2013 Mar 27.
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.
尽管过去十年癌症研究进展迅速，但在治疗晚期儿科实体瘤方面进展有限。酪氨酸激酶抑制是治疗人类恶性肿瘤的一种可行的治疗方法。然而，对于许多儿科实体瘤（如尤文肉瘤）的发育或维持至关重要的激酶知之甚少。我们使用荧光珠基技术对激活的酪氨酸激酶进行分析，发现粘着斑激酶（FAK，PTK2）是尤文肉瘤的一个候选靶点。FAK 是一种对细胞黏附、生长和存活至关重要的酪氨酸激酶。因此，它是癌症治疗的一个有吸引力的靶点。在这项研究中，我们表明 FAK 在原发性尤文肉瘤肿瘤样本中高度磷酸化，短发夹 RNA 下调 FAK 和使用 FAK 选择性激酶抑制剂 PF-562271 处理可损害尤文肉瘤细胞系的生长和集落形成。此外，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，我们表明小分子抑制 FAK 可减弱体内尤文肉瘤肿瘤的生长。由于 FAK 抑制剂目前正在进行成人恶性肿瘤的早期临床试验，这些发现可能与尤文肉瘤患者直接相关。
