Role of Focal Adhesion Kinase in Regulating YB–1–Mediated Paclitaxel Resistance in Ovarian Cancer

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Abstract

Background We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood.

Methods We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test.

Results We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 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 (χ ² = 37.7; P < .001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006).

Conclusions 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. 

Chemotherapy resistance confounds the effective treatment of ovarian and other cancers (1,2). Taxanes are commonly used for treatment of ovarian cancer, but unfortunately most cancers have inherent or acquired resistance (3). To date, the mechanisms by which tumor cells develop resistance to taxanes remain incompletely understood. Early studies showed that taxane resistance is a complex phenomenon (4), and underlying mechanisms are not fully known (5). Thus, new therapeutic approaches are needed to improve the outcome of women with ovarian cancer.

Among the many novel targets, focal adhesion kinase (FAK) is considered to be attractive for therapeutic development (6). FAK is a nonreceptor tyrosine kinase that plays a vital role in many oncogenic pathways (7). Increased FAK expression has been reported in a number of tumor types, including breast, colon, and ovarian cancers (8,9). We and others have previously reported that FAK inhibition can sensitize cancer cells to chemotherapy, but the underlying mechanisms are not well understood (10,11). In this study, we uncovered a novel pathway by which FAK inhibition restores the chemosensitivity of taxane-resistant cells to paclitaxel (PTX) by decreasing YB-1 phosphorylation and nuclear accumulation in an AKT-dependent manner...... 

"Although our findings provide a new understanding of FAK’s role in chemoresistance in ovarian cancer, some potential limitations should be considered. Whether the mechanism presented here is present in other tumor types is not known and will require additional work. Moreover, whether FAK inhibitors can effectively sensitize paclitaxel-resistant or paclitaxel-refractory tumors in clinical settings is also not known and will need to be tested in clinical trials. Nevertheless, we have uncovered a novel pathway by which FAK inhibition restores sensitivity of taxane-resistant cells to PTX by decreasing YB-1 phosphorylation and nuclear accumulation, and its downstream target gene-CD44. Future clinical studies should include mechanism-based pharmacodynamics studies to determine the biologically active doses in humans"