Therapeutic Efficacy of a Novel Focal Adhesion Kinase Inhibitor TAE226 in Ovarian Carcinoma

Abstract

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 taxaneresistant (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 dosedependent 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 tumorbearing 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. [Cancer Res 2007;67(22):10976-83]

Cytoskeletal reorganisation, 1α,25-dihydroxy vitamin D3 and human MG63 osteoblast maturation

“…This recently developed low molecular weight inhibitor is well characterised as preventing FAK activation via blockade of tyrosine phosphorylation (Halder et al, 2007;Shi et al, 2007). However the application of 500nM TAE226 did not inhibit MG63 maturation in response to LPA/ colchicine and D 3 (data not shown).…”

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

“…Early studies in ovarian cancer cell lines and xenografts demonstrated that knockdown of FAK expression enhanced docetaxel efficacy in docetaxelsensitive and docetaxel-resistant models in vitro and in vivo (31,32). Subsequently, TAE226, a TKI that targets FAK and IGF-1R, was demonstrated to enhance docetaxel cytotoxicity (33); however, at this point, development stalled due to the drug failing clinical trials. Other firstgeneration FAK TKIs had problems with compensatory upregulation of the FAK homolog, Pyk2, which affected clinical efficacy (34).…”

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

“…This approach is supported by studies that have reported sensitisation to 5-fluorouracil (5-FU) and a partial reversion of 5-FU resistance when FAK is suppressed (Chen et al 2009). Moreover, TAE226, a pharmacological inhibitor of FAK phosphorylation (Y397 and Y861), augments docetaxel sensitivity in taxane-resistant ovarian cancer cells (Halder et al 2007). In such contexts, FAK may represent a convergence point for multiple signalling pathways that may contribute to resistance, highlighting its potential importance as a therapeutic target.…”