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.

Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo

“…Previously, we have shown that INT2-31 penetrates tumor cells in vitro and can be identified in the tumor xenograft in vivo [30]. The additive effect of INT2-31 with gemcitabine, for inducing apoptosis and inhibiting tumor growth, demonstrates the possible use of INT2-31 in combination with standard chemotherapeutic regimens for pancreatic cancer.…”

The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and inhibits pancreatic cancer growth

“…Thus, allosteric FAK inhibitor Y15, targeting major autophosphorylation site of FAK Y397, which affects not only FAK kinase activity but, more importantly, FAK interactions with Src and PI3K, showed promising results in treatment of breast, pancreatic, colon and glioblastoma cancers [49]. PPI inhibitor NT2-31 targeted to the FAK-IGF-1R site of interaction dramatically reduced growth of melanoma, pancreatic and gastric cancers and show synergy with chemotherapy [22, 50]. …”

“…All staining procedures were done as previously described [50]. For detection, we used Vectastain Elite ABC kit (Vector Laboratories).…”

Focal adhesion complex proteins in epidermis and squamous cell carcinoma

“…58 Similarly, in melanoma, FAK interaction with the insulin-like growth factor receptor-1, IGF-1R, is necessary for downstream phosphorylation of Akt. 59 Abrogation of the FAK/IGF-1R interaction led to melanoma regression in an orthotopic mouse model. 59 Furthermore, in glioblastoma, FAK activity is dependent on PI3K/Akt activation, since knockdown of either the PIK3CA or PIK3R1 gene reduces FAK phosphorylation and tumor cell-invasive properties.…”

“…59 Abrogation of the FAK/IGF-1R interaction led to melanoma regression in an orthotopic mouse model. 59 Furthermore, in glioblastoma, FAK activity is dependent on PI3K/Akt activation, since knockdown of either the PIK3CA or PIK3R1 gene reduces FAK phosphorylation and tumor cell-invasive properties.…”