Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis

Clin Cancer Res. 2011 Jun 15;17(12):4042-51. doi: 10.1158/1078-0432.CCR-10-3387. Epub 2011 May 6.


Purpose: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth.

Experimental design: The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum.

Results: In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G(2)-M cell-cycle arrest, and (e) induction of anoikis.

Conclusions: This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer.

MeSH terms

  • Administration, Oral
  • Anilides / pharmacology*
  • Animals
  • Anoikis / drug effects*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Cycle / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Invasiveness / physiopathology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / pathology*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Quinolines / pharmacology*
  • Tumor Burden / drug effects
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays


  • Anilides
  • Antineoplastic Agents
  • GSK 1363089
  • Protein Kinase Inhibitors
  • Quinolines
  • Proto-Oncogene Proteins c-met
  • Vascular Endothelial Growth Factor Receptor-2