Focal adhesion kinase (FAK), a non-receptor kinase, is a key regulator of integrin and focal adhesion signaling required for cancer cell survival, cell migration, and cell invasion. Amplification/Overexpression of FAK occurs in a wide variety of human cancers, supporting a role in carcinogenesis. Moreover, preclinical studies using cancer models where FAK is genetically inhibited indicate that this kinase is a potential therapeutic target to interfere with cancer progression. However, very little progress has been made in the identification of chemical inhibitors for potential therapeutic applications, in contrast to other kinases. Herein, I report optimization of the high-throughput in vitro Glo kinase assay for screening inhibitors of FAK kinase activity. Screening a large library of small molecule chemicals using these assays identified at least twenty FAK inhibitors, including a new FAK inhibitor developed by Pfizer and undergoing human clinical trials, and the non-specific kinase inhibitor staurosporine. Molecular studies of selective FAK inhibitors are undergoing in my host laboratory. In addition to this in vitro assay, I established similar assays to examine FAK kinase and adapter function in intact cells. The latter consists of ErbB-transformed cells deficient in FAK, and their matched cells where wild-type or kinase-dead FAK was restored. Biological characterization of these models revealed that both FAK kinase and adaptor activities cooperate for the regulation of cell migration, cell invasion, and tumor formation.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111572 |
| Date | January 2008 |
| Creators | Cao, Yangxiezi. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 003163964, proquestno: AAIMR66874, Theses scanned by UMI/ProQuest. |
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