Research Papers:
Foretinib GSK1363089 induces p53dependent apoptosis in endometrial cancer
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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: [email protected]
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.