Authors: Deniz A. Ucar, Elena Kurenova, Timothy J. Garrett, William G. Cance, Carl Nyberg, Audrey Cox, Nicole Massoll, David A. Ostrov, Nicholas Lawrence, Saïd M. Sebti, Maria Zajac-Kaye and Steven N. Hochwald

Deniz A. Ucar

Department of Surgery; University of Florida College of Medicine; Gainesville, FL USA

Elena Kurenova

Department of Surgical Oncology; Roswell Park Cancer Institute; Buffalo, NY USA

Timothy J. Garrett

Clinical Research Center; University of Florida College of Medicine; Gainesville, FL USA

William G. Cance

Department of Surgical Oncology; Roswell Park Cancer Institute; Buffalo, NY USA

Carl Nyberg

Department of Surgery; University of Florida College of Medicine; Gainesville, FL USA

Audrey Cox

Department of Surgery; University of Florida College of Medicine; Gainesville, FL USA

Nicole Massoll

Department of Pathology, Immunology and Laboratory Medicine; University of Florida College of Medicine; Gainesville, FL USA

David A. Ostrov

Department of Pathology, Immunology and Laboratory Medicine; University of Florida College of Medicine; Gainesville, FL USA

Nicholas Lawrence

Department of Drug Discovery and Chemistry; Moffitt Cancer Center; Tampa, FL USA

Saïd M. Sebti

Department of Drug Discovery and Chemistry; Moffitt Cancer Center; Tampa, FL USA

Maria Zajac-Kaye

Department of Anatomy and Cell Biology; University of Florida College of Medicine; Gainesville, FL USA

Steven N. Hochwald

Corresponding author: steven.hochwald@roswellpark.org
Department of Surgical Oncology; Roswell Park Cancer Institute; Buffalo, NY USA

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.

Received: July 6, 2012; Accepted: July 24, 2012; Published Online: August 16, 2012

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