Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer.
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.
Affiliations 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).
Yu
Y
Kang
Wei
W
Hu
Cristina
C
Ivan
Heather J
HJ
Dalton
Takahito
T
Miyake
Chad V
CV
Pecot
Behrouz
B
Zand
Tao
T
Liu
Jie
J
Huang
Nicholas B
NB
Jennings
Rajesha
R
Rupaimoole
Morgan
M
Taylor
Sunila
S
Pradeep
Sherry Y
SY
Wu
Chunhua
C
Lu
Yunfei
Y
Wen
Jianfei
J
Huang
Jinsong
J
Liu
Anil K
AK
Sood
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016017:Odds Ratio; D009930:Organic Chemicals / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines; D013449:Sulfonamides; D023041:Xenograft Model Antitumor Assays; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D009930:Organic Chemicals; D011719:Pyrazines; D013449:Sulfonamides; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C584510:defactinib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel