Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities

Pascal Dao; Rafika Jarray; Nikaia Smith; Yves Lepelletier; Johanne Le Coq; Daniel Lietha; Réda Hadj-Slimane; Jean-Philippe Herbeuval; Christiane Garbay; Françoise Raynaud; Huixiong Chen

doi:10.1016/j.canlet.2014.03.007

Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities

Cancer Lett. 2014 Jun 28;348(1-2):88-99. doi: 10.1016/j.canlet.2014.03.007. Epub 2014 Mar 19.

Affiliations

¹ CNRS, UMR8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CBNIT, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
² UMR CNRS 8147, Université Paris Descartes, PRES Sorbonne Paris Cité, Hôpital Necker, 149, rue de Sèvre, 75743 Paris Cedex 15, France.
³ Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Calle Melchor Fernández Almagro 3, Madrid 28029, Spain.
⁴ Visiotact Pharma, 13-17, rue Moreau, 75012 Paris, France.
⁵ CNRS, UMR8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CBNIT, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France; School of Chemical Engineering and Light Industry, Guangdong University of Technology, No. 100 Waihuan Xi Road, Education Mega Center, Guangzhou 510006, China. Electronic address: [email protected].

PMID: 24657306
DOI: 10.1016/j.canlet.2014.03.007

Abstract

FAK and FGFR2 signaling pathways play important roles in cancer development, progression and tumor angiogenesis. PHM16 is a novel ATP competitive inhibitor of FAK and FGFR2. To evaluate the therapeutic efficacy of this agent, we examined its anti-angiogenic effect in HUVEC and its anti-tumor effect in different cancer cell lines. We showed PHM16 inhibited endothelial cell viability, adherence and tube formation along with the added ability to induce endothelial cell apoptosis. This compound significantly delayed tumor cell growth. Together, these data showed that inhibition of both FAK and FGFR2 signaling pathways can enhance anti-tumor and anti-angiogenic activities.

Keywords: Angiogenesis; Cancer; FAK; FGFR2; Inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / metabolism
Angiogenesis Inhibitors / pharmacology*
Apoptosis / drug effects
Binding Sites
Cell Adhesion / drug effects
Cell Cycle / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Enzyme Activation
Focal Adhesion Kinase 1 / antagonists & inhibitors*
Focal Adhesion Kinase 1 / metabolism
HCT116 Cells
Human Umbilical Vein Endothelial Cells / drug effects*
Human Umbilical Vein Endothelial Cells / enzymology
Human Umbilical Vein Endothelial Cells / pathology
Humans
Models, Molecular
Neoplasms / enzymology*
Neoplasms / pathology
Neovascularization, Physiologic / drug effects*
Phosphorylation
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 2 / metabolism
Signal Transduction / drug effects*

Substances

Angiogenesis Inhibitors
Protein Kinase Inhibitors
FGFR2 protein, human
Receptor, Fibroblast Growth Factor, Type 2
Focal Adhesion Kinase 1
PTK2 protein, human