Faculty Collaboration Database

Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer. J Natl Cancer Inst 2013 Oct 02;105(19):1485-95

Date

09/26/2013

Pubmed ID

24062525

Pubmed Central ID

PMC3787907

DOI

10.1093/jnci/djt210

Scopus ID

2-s2.0-84885440374 (requires institutional sign-in at Scopus site)   151 Citations

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.

Author List

Kang Y, Hu W, Ivan C, Dalton HJ, Miyake T, Pecot CV, Zand B, Liu T, Huang J, Jennings NB, Rupaimoole R, Taylor M, Pradeep S, Wu SY, Lu C, Wen Y, Huang J, Liu J, Sood AK

Author

Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents, Phytogenic
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Benzamides
Cell Line, Tumor
Cell Proliferation
Cell Survival
Drug Resistance, Neoplasm
Female
Focal Adhesion Kinase 1
Humans
Mice
Mice, Nude
Odds Ratio
Organic Chemicals
Ovarian Neoplasms
Paclitaxel
Phosphorylation
Proto-Oncogene Proteins c-akt
Pyrazines
Sulfonamides
Xenograft Model Antitumor Assays
Y-Box-Binding Protein 1