Oncotarget

Research Papers:

Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer

Yuhei Kogata, Tomohito Tanaka _, Yoshihiro J. Ono, Masami Hayashi, Yoshito Terai and Masahide Ohmichi

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:22769-22784. https://doi.org/10.18632/oncotarget.25232

Metrics: PDF 731 views  |   HTML 1144 views  |   ?  


Abstract

Yuhei Kogata1, Tomohito Tanaka1, Yoshihiro J. Ono1, Masami Hayashi1, Yoshito Terai1 and Masahide Ohmichi1

1Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Japan

Correspondence to:

Tomohito Tanaka, email: gyn123@osaka-med.ac.jp

Keywords: endometrial cancer; foretinib; p53; apoptosis

Received: September 08, 2017     Accepted: April 06, 2018     Published: April 27, 2018

ABSTRACT

Objective: Foretinib (GSK1363089 or XL880), which is an oral multikinase inhibitor developed to primarily target the hepatocyte growth factor (HGF)/Met signaling pathway, has shown anti-tumor effects against some cancers in preclinical and clinical studies.

Results: HGF/Met signaling in endometrial cancer cell lines was stimulated in an autocrine manner, and was essential for cell survival. Inhibiting the HGF/Met signaling with foretinib induced p53-dependent apoptosis in endometrial cancer cell lines in vitro. Foretinib also showed significant anti-cancer effects in vivo in experiments using cell tumor xenografts. p53 mutations were observed in 37 (10.8%) of 344 endometrial cancer specimens.

Conclusion: The HGF/Met-MAPK/PI3K pathway in endometrial cancer is activated by HGF in an autocrine manner. Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib was found to exert greater anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations. Our immunochemical analysis revealed that foretinib-induced p53-dependent apoptosis can be expected to have therapeutic potential in approximately 90% of endometrial cancer patients.

Methods: We evaluated the HGF/Met signaling pathway in endometrial cancer cell lines and assessed the anti-cancer effects of foretinib using in vitro and in vivo experimental models. Furthermore, endometrial cancer specimens were subjected to an immunohistochemical analysis.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 25232