Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 105, Issue 19, Pages 1485-1495Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djt210
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Funding
- National Institutes of Health [CA 109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599]
- Ovarian Cancer Research Fund, Inc.
- Cancer Prevention and Research Institute of Texas [RP110595]
- Department of Defense [OC073399, W81XWH-10-1-0158, BC085265]
- Zarrow Foundation
- Marcus Foundation
- Blanton-Davis Ovarian Cancer Research Program
- Betty Anne Asche Murray Distinguished Professorship
- NCI-DHHS-NIH T32 Training Grant [T32 CA101642]
- NCI institutional Core Grant [CA16672]
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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 (chi(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.
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