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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
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Focal Adhesion Protein-Tyrosine Kinases / metabolism
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Humans
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Mice
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Mice, Nude
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Molecular Structure
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology*
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / metabolism
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Purine Nucleosides / chemistry
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Purine Nucleosides / pharmacology*
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Receptor, IGF Type 1 / antagonists & inhibitors*
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Receptor, IGF Type 1 / metabolism
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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4-(methylthio)-7-(5-O-phosphonoribofuranosyl)-7H-pyrrolo(2,3-d)pyrimidine
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Purine Nucleosides
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Proto-Oncogene Proteins c-met
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Receptor, IGF Type 1
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Focal Adhesion Protein-Tyrosine Kinases