Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth.

Abstract

FAK (focal adhesion kinase) and IGF-1R (insulin-like growth factor receptor-1) directly interact with each other and thereby activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function has been shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. As a novel approach in human melanoma, we evaluated the effect of a small-molecule compound that disrupts the protein interaction of FAK and IGF-1R. Previously, using virtual screening and functional testing, we identified a lead compound (INT2-31) that targets the known FAK-IGF-1R protein interaction site. We studied the ability of this compound to disrupt FAK-IGF-1R protein interactions, inhibit downstream signaling, decrease human melanoma cell proliferation, alter cell cycle progression, induce apoptosis and decrease tumor growth in vivo. INT2-31 blocked the interaction of FAK and IGF-1R in vitro and in vivo in melanoma cells and tumor xenografts through precluding the activation of IRS-1, leading to reduced phosphorylation of AKT upon IGF-1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05-10 μM). More importantly, 15 mg/kg of INT2-31 given for 21 d via intraperitoneal injection disrupted the interaction of FAK and IGF-1R and effectively decreased phosphorylation of tumor AKT, resulting in significant melanoma tumor regression in vivo. Our data suggest that the FAK-IGF-1R protein interaction is an important target, and disruption of this interaction with a novel small molecule (INT2-31) has potential anti-neoplastic therapeutic effects in human melanoma.

• Authors: Deniz A Ucar, Elena Kurenova, Timothy J Garrett, William G Cance, Carl Nyberg, Audrey Cox, Nicole Massoll, David A Ostrov, Nicholas Lawrence, Said M Sebti, Maria Zajac-Kaye, Steven N Hochwald
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 11 Issue 17 Pg. 3250-9 (Sep 01 2012) ISSN: 1551-4005 [Electronic] United States
• PMID: 22894899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 4-(methylthio)-7-(5-O-phosphonoribofuranosyl)-7H-pyrrolo(2,3-d)pyrimidine
• Protein Kinase Inhibitors
• Purine Nucleosides
• RNA, Small Interfering
• Receptor, IGF Type 1
• Focal Adhesion Kinase 1
• PTK2 protein, human

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Flow Cytometry
• Focal Adhesion Kinase 1 (metabolism)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• In Situ Nick-End Labeling
• Melanoma (drug therapy, metabolism, physiopathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Purine Nucleosides (pharmacology, therapeutic use)
• RNA, Small Interfering (genetics)
• Receptor, IGF Type 1 (metabolism)
• Signal Transduction (drug effects, physiology)