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

We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood. We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-...

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Vydáno v:	JNCI : Journal of the National Cancer Institute Ročník 105; číslo 19; s. 1485
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 02.10.2013
Témata:	Animals Antineoplastic Agents, Phytogenic - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis - drug effects Benzamides Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Drug Resistance, Neoplasm Female Focal Adhesion Kinase 1 - antagonists & inhibitors Focal Adhesion Kinase 1 - metabolism Humans Mice Mice, Nude Odds Ratio Organic Chemicals - pharmacology Ovarian Neoplasms - drug therapy Ovarian Neoplasms - enzymology Paclitaxel - pharmacology Phosphorylation - drug effects Proto-Oncogene Proteins c-akt - metabolism Pyrazines Sulfonamides Xenograft Model Antitumor Assays Y-Box-Binding Protein 1 - metabolism
ISSN:	1460-2105, 1460-2105
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Shrnutí:	We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood. 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. 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). 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1460-2105 1460-2105
DOI:	10.1093/jnci/djt210