Targeting IRS-1/2 in uveal melanoma inhibitsin vitrocell growth, survival and migration, andin vivotumor growth

Abstract

AbstractUveal melanoma (UM) originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of insulin-like growth factor −1 and its receptor (IGF-1/IGF-1R) signaling in UM. We found that the insulin receptor substrate −1 (IRS-1) is overexpressed in UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2 in blocking this pathway in UM. NT157 treatment in UM cells resulted in reduced cell survival and migration, and increased apoptosis. This treatment also significantly inhibited UM tumor growthin vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating thein vitroeffect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell survival, migrationin vitroand tumor growthin vivovia inhibiting IGF-1 signaling in UM.