title: Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression.
abstract: Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the peri-ovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer.
authors.affiliation: Department of Reproductive Medicine, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Kristy K
authors.initials: KK
authors.lastname: Ward
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tancioni
authors.forename: Christine
authors.initials: C
authors.lastname: Lawson
authors.forename: Nichol L G
authors.initials: NL
authors.lastname: Miller
authors.forename: Christine
authors.initials: C
authors.lastname: Jean
authors.forename: Xiao Lei
authors.initials: XL
authors.lastname: Chen
authors.forename: Sean
authors.initials: S
authors.lastname: Uryu
authors.forename: Josephine
authors.initials: J
authors.lastname: Kim
authors.forename: David
authors.initials: D
authors.lastname: Tarin
authors.forename: Dwayne G
authors.initials: DG
authors.lastname: Stupack
authors.forename: Steven C
authors.initials: SC
authors.lastname: Plaxe
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
mesh_terms: D002455:Cell Division / Q000187:drug effects*; D018450:Disease Progression; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051416:Focal Adhesion Protein-Tyrosine Kinases