Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma.
Focal adhesion kinase (FAK) overexpression is frequently found in ovarian and other cancers and is predictive of poor clinical outcome. In the current study, we characterized the biological and therapeutic effects of a novel FAK inhibitor, TAE226. Taxane-sensitive (SKOV3ip1 and HeyA8) and taxane-resistant (HeyA8-MDR) cell lines were used for in vitro and in vivo therapy experiments using TAE226 alone and in combination with docetaxel. Assessment of cytotoxicity, cell proliferation [proliferating cell nuclear antigen (PCNA)], angiogenesis (CD31), and apoptosis (terminal nucleotidyl transferase-mediated nick end labeling) were done by immunohistochemistry and immunofluorescence. In vitro, TAE226 inhibited the phosphorylation of FAK at both Y397 and Y861 sites, inhibited cell growth in a time- and dose-dependent manner, and enhanced docetaxel-mediated growth inhibition by 10- and 20-fold in the taxane-sensitive and taxane-resistant cell lines, respectively. In vivo, FAK inhibition by TAE226 significantly reduced tumor burden in the HeyA8, SKOV3ip1, and HeyA8-MDR models (46-64%) compared with vehicle-treated controls. However, the greatest efficacy was observed with concomitant administration of TAE226 and docetaxel in all three models (85-97% reduction, all P values <0.01). In addition, TAE226 alone and in combination with chemotherapy significantly prolonged survival in tumor-bearing mice. Even in larger tumors, combination therapy with TAE226 and docetaxel resulted in tumor regression. The therapeutic efficacy was related to reduced pericyte coverage, induction of apoptosis of tumor-associated endothelial cells, and reduced microvessel density and tumor cell proliferation. The novel FAK inhibitor, TAE226, offers an attractive therapeutic approach in ovarian carcinoma.
Halder
Jyotsnabaran
J
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Lin
Yvonne G
YG
Merritt
William M
WM
Spannuth
Whitney A
WA
Nick
Alpa M
AM
Honda
Toshiyuki
T
Kamat
Aparna A
AA
Han
Liz Y
LY
Kim
Tae Jin
TJ
Lu
Chunhua
C
Tari
Ana M
AM
Bornmann
William
W
Fernandez
Ariel
A
Lopez-Berestein
Gabriel
G
Sood
Anil K
AK
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism
D004791:Enzyme Inhibitors; D009025:Morpholines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; C524632:TAE226; D051416:Focal Adhesion Protein-Tyrosine Kinases