Focal Adhesion Kinase Regulates YB-1–Mediated Paclitaxel Resistance in Ovarian Cancer

Get Permission

It has been found that focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to the effects of taxanes. In a study reported in the Journal of the National Cancer Institute, Kang and colleagues evaluated the response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). Reverse-phase protein arrays were used to identify novel downstream targets in taxane-resistant cell lines, and clinical and pathologic data were correlated with nuclear and cytoplasmic expression of FAK and YB-1, a mediator of taxane resistance present at high levels in taxane-resistant cells, in 105 ovarian cancer samples. 

It was found that the FAK inhibitor blocked FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of FAK inhibitor and paclitaxel reduced proliferation and increased apoptosis, resulting in 92.7% to 97.9% reductions in tumor weight. 

Reverse-phase protein array data showed that the FAK inhibitor reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression, and coexpression of nuclear FAK and YB-1 was associated with significantly worse median overall survival (24.9 vs 67.3 months, hazard ratio = 2.64, P = .006). 

The investigators concluded, “We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1-mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.” 

Kang Y, et al: J Natl Cancer Inst 105:1485-1495, 2013




By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.