| Autor: |
Kang, Yu, Hu, Wei, Ivan, Cristina, Dalton, Heather J., Miyake, Takahito, Pecot, Chad V., Zand, Behrouz, Liu, Tao, Huang, Jie, Jennings, Nicholas B., Rupaimoole, Rajesha, Taylor, Morgan, Pradeep, Sunila, Wu, Sherry Y., Lu, Chunhua, Wen, Yunfei, Huang, Jianfei, Liu, Jinsong, Sood, Anil K. |
| Předmět: |
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| Zdroj: |
JNCI: Journal of the National Cancer Institute; 10/2/2013, Vol. 105 Issue 19, p1485-1495, 11p, 1 Chart, 6 Graphs |
| Abstrakt: |
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 (χ2 = 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. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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