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

The abstract, as originally published online, read as follows: Previously, we have shown that focal adhesion kinase (FAK) and insulin-like growth factor receptor-1 (IGF-1R) directly interact with each other and, thereby, activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function have shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. In this study, as a novel approach in human melanoma, we evaluated the effect of a small molecule compound that disrupts the interaction of FAK and IGF-1R. 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, induce apoptosis and decrease tumor growth in vivo. Based on glutathione S-transferase pulldowns with purified protein fragments of FAK and IGF-1R and from coimmunoprecipitation assays from melanoma cells, INT2-31 blocked the interaction of FAK and IGF-1R and precluded activation of Insulin receptor substrate-1 leading to reduced phosphorylation of AKT upon IGF1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05–10 lM). More importantly, 15 mg/kg of INT2-31 given for 21 days 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 (P , 0.05). Our data suggest that FAK-IGF-1R protein interaction can be identified as an important target and disruption of this interaction with a small molecule has potential anti-neoplastic therapeutic effects in human melanoma.