Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth.
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.
Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
Deniz A
DA
Ucar
Elena
E
Kurenova
Timothy J
TJ
Garrett
William G
WG
Cance
Carl
C
Nyberg
Audrey
A
Cox
Nicole
N
Massoll
David A
DA
Ostrov
Nicholas
N
Lawrence
Said M
SM
Sebti
Maria
M
Zajac-Kaye
Steven N
SN
Hochwald
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011684:Purine Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
C577148:4-(methylthio)-7-(5-O-phosphonoribofuranosyl)-7H-pyrrolo(2,3-d)pyrimidine; D047428:Protein Kinase Inhibitors; D011684:Purine Nucleosides; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human