Abstract 3582: Targeting the FAK amino terminus F2 subdomain to disrupt growth factor receptor protein interactions, signaling and function

Abstract

Abstract Introduction: Focal adhesion kinase (FAK), IGF-1R and the c-MET are tyrosine kinases that induce cell proliferation, invasion, metastases and survival. We have previously shown that FAK physically interacts with growth factor receptors in pancreatic cancer cells and is involved in tumor progression. Since IGF-1R and c-MET have significant structural similarity, we hypothesize that both interact with a similar conserved amino acid “patch” on FAK. We also hypothesize that this patch can be targeted with small molecules to inhibit pancreatic cancer essential signaling pathways and induce apoptosis. Methods: Based on Lipinski rules, we screened a chemical library of 240,000 compounds against a conserved patch on the F2 subdomain of FAK using in silico high throughput screening. We obtained the top scoring compounds from the National Cancer Institute Developmental Therapeutics Program and evaluated their effects on: 1) FAK protein interactions with c-MET and IGF-1R, 2) FAK, IGF-1R and c-MET kinase activity, 3)cell viability and apoptosis, and 4) growth of Panc-1 and Miapaca-2 pancreatic cancer cells in both orthotopic and direct xenograft mouse tumor models. Results: Based on co-immunoprecipitation assays, our lead compound blocked the interaction of FAK with both c-MET and IGF-1R in pancreatic cancer cells, without altering their kinase activity. Treatment with our lead compound led to decreased phosphorylation of AKT, inhibited cell viability and induced apoptosis in a dose-dependent manner (range 2-20μM). In addition, the combination of our lead compound with either 5-FU or gemcitabine chemotherapy resulted in a synergistic decrease in pancreatic cancer cell viability. More importantly, 10mg/kg of lead compound via subcutaneous injection, effectively (p<0.05) caused pancreatic tumor regression in vivo in both an orthotopic and direct xenograft model of pancreatic cancer. Conclusions: Our data suggest that targeting the protein interactions of FAK with growth factor receptors including c-MET and IGF-1R has specific therapeutic effects that can increase the sensitivity of pancreatic cancer cells to conventional chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3582. doi:10.1158/1538-7445.AM2011-3582