Title:Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo
Volume: 13
Issue: 4
Author(s): Deniz A. Ucar, Andrew T. Magis, Di-Hua He, Nicholas J. Lawrence, Said M. Sebti, Elena Kurenova, Maria Zajac-Kaye, Jianliang Zhang and Steven N. Hochwald
Affiliation:
Keywords:
FAK, IGF-1R, Pancreatic cancer, Protein interactions
Abstract: Pancreatic cancer is one of the most lethal diseases with no effective treatment. Previously, we have shown that FAK is
overexpressed in pancreatic cancer and plays a key role in cancer cell survival and proliferation. FAK has been shown to interact with
growth factor receptors including cMET and IGF-1R. As a novel therapeutic approach, we targeted the protein interaction of FAK with
growth factor receptors to block tumor growth, alter signaling pathways and sensitize cells to chemotherapy. We have selected a small
molecule compound (INT2-31) that decreases phosphorylation of AKT via disrupting interaction of FAK with cMET and IGF-1R. Our
results demonstrate that interaction of a small molecule compound with FAK decreases phosphorylation of FAK Y397 while increasing
FAK Y407 phosphorylation, without inhibiting the kinase activity of FAK and dramatically reduces downstream signaling to AKT. Our
lead compound, INT2-31, demonstrates significant inhibition of tumor cell growth in two orthotopic models of pancreatic cancer. In
addition, INT2-31increases sensitivity to gemcitabine chemotherapy in a direct fresh biopsy xenograft model of pancreatic cancer
growth.
