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

Yuhei Kogata1, Tomohito Tanaka1, Yoshihiro J Ono1

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

Oncotarget
|June 2, 2018
PubMed
Abstract

Insights

Foretinib effectively targets the HGF/Met pathway in endometrial cancer, inducing p53-dependent apoptosis. This multikinase inhibitor shows therapeutic potential for most patients, particularly those with wild-type p53.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hepatocyte growth factor (HGF)/Met signaling is crucial for endometrial cancer cell survival.
  • This pathway is often activated in an autocrine manner in endometrial cancer.
  • Foretinib is an oral multikinase inhibitor targeting the HGF/Met pathway.

Purpose of the Study:

  • To evaluate the role of HGF/Met signaling in endometrial cancer.
  • To assess the anti-cancer effects of foretinib in endometrial cancer.
  • To determine the predictive value of p53 status for foretinib efficacy.

Main Methods:

  • In vitro and in vivo studies using endometrial cancer cell lines and xenografts.
  • Evaluation of HGF/Met signaling pathway.
  • Immunohistochemical analysis of endometrial cancer specimens.

Main Results:

  • HGF/Met signaling is essential for endometrial cancer cell survival.
  • Foretinib inhibits HGF/Met signaling, inducing p53-dependent apoptosis.
  • Foretinib demonstrated significant anti-cancer effects in vitro and in vivo.
  • p53 mutations were found in 10.8% of endometrial cancer specimens.

Conclusions:

  • The HGF/Met-MAPK/PI3K pathway is activated by HGF in an autocrine manner in endometrial cancer.
  • Foretinib induces p53-dependent apoptosis by inhibiting Met phosphorylation.
  • Foretinib exhibits greater efficacy in endometrial cancers with wild-type p53.
  • Therapeutic potential for foretinib-induced apoptosis is estimated in approximately 90% of endometrial cancer patients.
Keywords:
apoptosisendometrial cancerforetinibp53

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