br Conclusion BMS exhibits antitumor effects on

Conclusion: BMS-777607 exhibits antitumor effects on ovarian cancer Tigecycline that constitutively express c-MET through c-MET signaling blockade and the inhibition of Aurora B activity. Combination treatments to enhance the effects of BMS-777607 warrant investigation in the future. © 2018 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide [1]. The current standard treatment for EOC is a combination of optimal cytoreduction and chemotherapy [2]. Because of the absence of specific symptoms during early stages and a shortage of reliable markers, most cases of epithelial ovarian cancer are diagnosed at an advanced stage at which disease recurrence is high and the survival rate is low [3e5]. Thus, the development of novel therapeutic strategies for this recalcitrant disease is necessary.
* Corresponding author. Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei, Taiwan. Fax: þ886 2 25232448.
E-mail address: clchang@mmc.edu.tw (C.-L. Chang). 1 Chao-Chih Wu and Chia-Sui Weng contributed equally to this work. 
The use of small molecules, such as tyrosine kinase inhibitors (TKIs), to block the signaling cascade involved in tumorigenesis is a robust targeted therapy for cancer treatment [6]. For example, Erlotinib and Gefitinib, which target epidermal growth factor re-ceptors (EGFRs), were approved by the Food and Drug Adminis-tration for the treatment of non-small-cell lung cancer [7] and HER2/neu blockade was approved for breast cancer therapy [8]. However, there had not been a promising target therapy in treating ovarian cancer and TKIs have not been used for the treatment of ovarian cancer. In this study we aimed to design a pre-clinical study to experiment on this potential target to scrutinize its antitumor effect. c-MET is a receptor tyrosine kinase that plays a crucial role in tumorigenesis [9]. c-MET over expression has been considered a prognostic marker for ovarian cancer [10]. The receptor is activated on binding with its ligand, hepatocyte growth factor (HGF), and activates the ras-mitogen-activated protein kinase (MAPK), phos-phatidylinositol 3-kinase (PI3K), and signal transducers and
1028-4559/© 2018 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
activators of transcription signaling pathways [11,12]. All these signals collectively induce cell proliferation and dissemination. Thus, targeting c-MET by blocking the interaction between HGF and c-MET is considered as an effective strategy for the management of ovarian cancer. Aberrant activation of c-MET may be due to the overexpression of its ligand. However, a clinical trial using hu-manized IgG2 directed against HGF did not reveal any antitumor effect of this strategy on ovarian cancer [13]. HGF is expressed at high levels in normal ovarian stromal fibroblasts but not in cancer-associated fibroblasts [14]. These results indicate that c-MET acti-vation may be independent of HGF in ovarian cancer. Furthermore, point mutations of the MET gene [15] or activation of other re-ceptors [16], such as EGFR, semaphorin 4D receptor, or a5-integrin, can activate Met. Thus, targeting c-MET directly may be suitable for ovarian cancer treatment.
BMS-777607 is an ATP-competitive MET kinase inhibitor that primarily targets several MET family members, including RON, c-MET, Axl, and Tyro3 [17]. This molecule has been demonstrated to suppress HGF-stimulated prostate cancer metastasis [18]. BMS-777607 also suppressed c-MET auto-phosphorylation and down-stream signaling in PC-3 cells with constitutively activated c-MET [19]. This implies that BMS-777607 could be used for inhibiting HGF-independent c-MET auto-phosphorylation for treating ovarian cancer. In addition to the MET family, BMS-777606 has been re-ported to block Mer, Flt-3, Aurora B, Lck, and vascular endothelial growth factor (VEGF) receptor 2 at higher concentrations [17]. The inhibition of Aurora B by BMS-777607 was also reported to induce polyploidy in breast cancer cell lines [20]. These results demon-strate that BMS-777607 is a multikinase inhibitor that can inhibit carcinogenesis through different mechanisms.
In this study, we used a c-MET constitutive phosphorylation tumor model to mimic HGF-independent activation and evaluated the antitumor effects of BMS-777607 on ovarian cancer cells. Ovarian cancer cells with constitutively activated c-MET were first screened. The viabilities of cells with constitutively activated c-MET and overexpressed c-MET as well as of c-MET-negative cells were compared after BMS-777607 treatment. The phenotypes of BMS-777607-treated ovarian cancer cells, including cell apoptosis, migration, and polyploidy, were further evaluated to determine the effects of BMS-777607. In addition, the antitumor effects of BMS-777607 were further demonstrated in xenographic mouse tumor systems. In summary, this study demonstrated that BMS-777607 affects tumorigenesis through the inhibition of multikinases.