Targeting the C-terminal focal adhesion kinase scaffold in pancreatic cancer

• C-terminal FAK scaffold inhibitor C10 selectively targets cancer cells with high FAK-Y925 and VEGFR3 expression levels.
• FAK inhibitor C10 inhibited FAK and VEGFR3 signaling and decreased cancer cell motility and invasion.
• FAK inhibitor C10 exerts anti-tumor and anti-angiogenic effects.
• Treatment with FAK inhibitor C10 decreased interstitial fluid pressure.

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.