Abstract
ObjectiveForetinib (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.ResultsHGF/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.ConclusionThe 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.MethodsWe 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.
Highlights
It has been estimated that more than sixty thousand women will be newly diagnosed with uterine corpus cancer, and that this cancer will be the cause of death in over ten thousand women in the United States in 2016 [1]
Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53dependent 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 p53dependent apoptosis can be expected to have therapeutic potential in approximately 90% of endometrial cancer patients
Summary
It has been estimated that more than sixty thousand women will be newly diagnosed with uterine corpus cancer, and that this cancer will be the cause of death in over ten thousand women in the United States in 2016 [1]. Endometrial carcinoma is the sixth most common cancer in women, and three-quarters of women who are diagnosed with endometrial cancer are postmenopausal. 80% of endometrial carcinomas are type I tumors, which are endometrioid carcinomas. 20% of endometrial carcinomas are type II tumors, which are nonendometrioid and largely serous carcinomas. Advanced endometrial carcinoma has basically been treated with radiation therapy as postoperative management; in recent years, radiation therapy has been compared to postoperative adjuvant chemotherapy and clinical trials of chemotherapy regimens have been www.oncotarget.com conducted. The prognosis of advanced endometrial carcinoma is still poor, and molecular targeted therapy is attracting attention as a new treatment approach [3,4,5]
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