High-throughput tyrosine kinase activity profiling identifies FAK as a candidate therapeutic target in Ewing sarcoma.

Abstract

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.

• Authors: Brian D Crompton, Anne L Carlton, Aaron R Thorner, Amanda L Christie, Jinyan Du, Monica L Calicchio, Miguel N Rivera, Mark D Fleming, Nancy E Kohl, Andrew L Kung, Kimberly Stegmaier
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 9 Pg. 2873-83 (May 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23536552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein-Tyrosine Kinases
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Adult
• Animals
• Apoptosis
• Cell Line, Tumor
• Cell Survival
• Child
• Down-Regulation
• Female
• Flow Cytometry (methods)
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Immunohistochemistry (methods)
• Lentivirus (genetics)
• Mice
• Mice, Nude
• Phosphorylation
• Protein-Tyrosine Kinases (metabolism)
• Sarcoma, Ewing (drug therapy, metabolism)
• Treatment Outcome