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J Natl Cancer Inst. 2013 Oct 2;105(19):1485-95. doi: 10.1093/jnci/djt210. Epub 2013 Sep 23.

Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer.

Author information

  • 1Affiliations of authors: Department of Gynecologic Oncology and Repro ductive Medicine (YK, WH, CI, CVP, HJD, BZ, TL, JH, NBJ, RR, MT, TM, SP, SYW, CL, YW, AKS), Center for RNAi and Non-Coding RNA (CI, AKS), Department of Pathology (JH, JL), and Department of Cancer Biology (AKS), The University of Texas MD Anderson Cancer Center, Houston, TX; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical College of Fudan University, Shanghai, China (YK); Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (TL).

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 (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.

Comment in

PMID:
24062525
[PubMed - indexed for MEDLINE]
PMCID:
PMC3787907
[Available on 2014/10/2]
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