Inhibiting the Interaction of Cmet and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in Vitro and in Vivo.

Deniz A. Ucar,Andrew T. Magis,Di-Hua He,Nicholas J. Lawrence,Said M. Sebti,Elena Kurenova,Maria Zajac-Kaye,Jianliang Zhang,Steven N. Hochwald

Anti-cancer Agents in Medicinal Chemistry（2013）SCI 4区

Univ Florida

Cited 26|Views16

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, INT2-31 increases sensitivity to gemcitabine chemotherapy in a direct fresh biopsy xenograft model of pancreatic cancer growth.

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Key words

FAK,IGF-1R,Pancreatic cancer,Protein interactions

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