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