Journal
CANCER LETTERS
Volume 353, Issue 2, Pages 281-289Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.07.032
Keywords
Focal adhesion kinase; Vascular endothelial growth factor receptor-3; Focal adhesion targeting domain; FAK scaffold inhibition; Pancreatic cancer
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Funding
- National Cancer Institute [RO1-CA65910]
- Photolitec Grant
- ROSWELL PARK CANCER INSTITUTE
- NCI Cancer Center [CA016156]
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Preliminary studies in our laboratory have demonstrated the importance of both the NH2 and COOH terminus scaffolding functions of focal adhesion kinase (FAK). Here, we describe a new small molecule inhibitor, C10, that targets the FAK C-terminus scaffold. C10 showed marked selectivity for cells overexpressing VEGFR3 when tested in isogenic cell lines, MCF7 and MCF7-VEGFR3. C10 preferentially inhibited pancreatic tumor growth in vivo in cells with high FAK-Y925 and VEGFR3 expression. Treatment with C10 led to a significant inhibition in endothelial cell proliferation and tumor endothelial and lymphatic vessel density and decrease in interstitial fluid pressure. These results highlight the underlying importance of targeting the FAK scaffold to treat human cancers. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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