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

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• Focal adhesion kinase (FAK) plays a crucial role in cellular processes through its NH2 and COOH terminus scaffolding functions.
• Targeting FAK's scaffolding ability is a potential strategy for cancer therapy.

Purpose of the Study:

• To introduce a novel small molecule inhibitor, C10, designed to target the FAK C-terminus scaffold.
• To evaluate the efficacy and selectivity of C10 in inhibiting cancer growth, particularly in VEGFR3-overexpressing cells.

Main Methods:

• Development of a small molecule inhibitor, C10, targeting the FAK C-terminus.
• Testing C10 selectivity in isogenic cell lines (MCF7 and MCF7-VEGFR3) with varying VEGFR3 expression.
• In vivo studies using pancreatic tumor models with high FAK-Y925 and VEGFR3 expression.
• Assessment of C10's effects on endothelial cell proliferation, tumor vascularity (endothelial and lymphatic), and interstitial fluid pressure.

Main Results:

• C10 demonstrated marked selectivity for cells overexpressing VEGFR3.
• C10 preferentially inhibited pancreatic tumor growth in vivo in models with high FAK-Y925 and VEGFR3 expression.
• Treatment with C10 significantly reduced endothelial cell proliferation, tumor endothelial and lymphatic vessel density, and interstitial fluid pressure.

Conclusions:

• Targeting the FAK scaffold with small molecule inhibitors like C10 is a viable strategy for cancer treatment.
• C10 shows significant anti-tumor activity, particularly in cancers with high FAK-Y925 and VEGFR3 expression, by inhibiting angiogenesis and improving the tumor microenvironment.