Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors.

Abstract

The present study sought to determine the anti-tumor effects of OXA-11, a potent, novel small-molecule amino pyrimidine inhibitor (1.2 pM biochemical IC(50)) of focal adhesion kinase (FAK). In studies of cancer cell lines, OXA-11 inhibited FAK phosphorylation at phospho-tyrosine 397 with a mechanistic IC(50) of 1 nM in TOV21G tumor cells, which translated into functional suppression of proliferation in 3-dimensional culture with an EC(50) of 9 nM. Studies of OXA-11 activity in TOV21G tumor-cell xenografts in mice revealed a pharmacodynamic EC(50) of 1.8 nM, indicative of mechanistic inhibition of pFAK [Y397] in these tumors. OXA-11 inhibited TOV21G tumor growth in a dose-dependent manner and also potentiated effects of cisplatin on tumor cell proliferation and apoptosis in vitro and on tumor growth in mice. Studies of pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice revealed OXA-11 suppression of pFAK [Y397] and pFAK [Y861] in tumors and liver. OXA-11 given daily from age 14 to 17 weeks reduced tumor vascularity, invasion, and when given together with the anti-VEGFR-2 antibody DC101 reduced the incidence, abundance, and size of liver metastases. Liver micrometastases were found in 100 % of mice treated with vehicle, 84 % of mice treated with OXA-11, and 79 % of mice treated with DC101 (19-24 mice per group). In contrast, liver micrometastases were found in only 52 % of 21 mice treated with OXA-11 plus DC101, and those present were significantly smaller and less numerous. Together, these findings indicate that OXA-11 is a potent and selective inhibitor of FAK phosphorylation in vitro and in vivo. OXA-11 slows tumor growth, potentiates the anti-tumor actions of cisplatin and--when combined with VEGFR-2 blockade--reduces metastasis of pancreatic neuroendocrine tumors in RIP-Tag2 mice.

• Authors: Ingrid Moen, Matthew Gebre, Vanesa Alonso-Camino, Debbie Chen, David Epstein, Donald M McDonald
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 32 Issue 8 Pg. 799-817 (Dec 2015) ISSN: 1573-7276 [Electronic] Netherlands
• PMID: 26445848 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor Receptor-2
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Animals
• Cell Proliferation
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Humans
• Liver Neoplasms (secondary)
• Mice
• Neoplasm Invasiveness
• Neoplasm Micrometastasis
• Neuroendocrine Tumors (blood supply, drug therapy, pathology)
• Pancreatic Neoplasms (blood supply, drug therapy, pathology)
• Phosphorylation
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, physiology)