Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment.

Abstract

Current therapies for pancreatic ductal adenocarcinoma (PDA) target individual tumor cells. Focal adhesion kinase (FAK) is activated in PDA, and levels are inversely associated with survival. We investigated the effects of PF-562,271 (a small-molecule inhibitor of FAK/PYK2) on (i) in vitro migration, invasion, and proliferation; (ii) tumor proliferation, invasion, and metastasis in a murine model; and (iii) stromal cell composition in the PDA microenvironment. Migration assays were conducted to assess tumor and stromal cell migration in response to cellular factors, collagen, and the effects of PF-562,271. An orthotopic murine model was used to assess the effects of PF-562,271 on tumor growth, invasion, and metastasis. Proliferation assays measured PF-562,271 effects on in vitro growth. Immunohistochemistry was used to examine the effects of FAK inhibition on the cellular composition of the tumor microenvironment. FAK and PYK2 were activated and expressed in patient-derived PDA tumors, stromal components, and human PDA cell lines. PF-562,271 blocked phosphorylation of FAK (phospho-FAK or Y397) in a dose-dependent manner. PF-562,271 inhibited migration of tumor cells, cancer-associated fibroblasts, and macrophages. Treatment of mice with PF-562,271 resulted in reduced tumor growth, invasion, and metastases. PF-562,271 had no effect on tumor necrosis, angiogenesis, or apoptosis, but it did decrease tumor cell proliferation and resulted in fewer tumor-associated macrophages and fibroblasts than control or gemcitabine. These data support a role for FAK in PDA and suggest that inhibitors of FAK may contribute to efficacious treatment of patients with PDA.

• Authors: Jayme B Stokes, Sara J Adair, Jill K Slack-Davis, Dustin M Walters, Robert W Tilghman, E Dan Hershey, Bryce Lowrey, Keena S Thomas, Amy H Bouton, Rosa F Hwang, Edward B Stelow, J Thomas Parsons, Todd W Bauer
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 11 Pg. 2135-45 (Nov 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21903606 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide
• Protein Kinase Inhibitors
• Sulfonamides
• Receptor Protein-Tyrosine Kinases
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Pancreatic Ductal (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors)
• Humans
• Indoles (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology, therapeutic use)
• Tumor Microenvironment (drug effects)