Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth

SIMPLE SUMMARY: Uveal melanoma (UM) is the most common eye cancer in adults and its spreading to the liver has poor outcomes for the patients. There is currently only one therapeutic option for treating UM, hence, there is a need for a better understanding of the biology of UM metastatic spreading in order to develop novel therapies. We think that the growth factors originating from the liver contribute to UM metastasis, and here, we have investigated the role of insulin-like growth factor and its receptor (IGF-1 and IGF-1R) signaling in UM growth. We found that inhibiting the IGF-1R substrates, insulin receptor substrates-1/2 (IRS-1/2) through a small molecule inhibitor, NT157, resulted in a reduction of cell survival, migration and increased apoptosis in multiple UM cell lines. Importantly, in our in vivo models, we have shown that N157 treatment reduces UM tumor growth, indicating that targeting IGF-1/IGF-1R signaling could be a potential therapeutic strategy. ABSTRACT: Uveal melanoma 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 IGF-1/IGF-1R signaling in UM. Here, we found that IRS-1, the insulin receptor substrate, is overexpressed in both 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 of multiple UM cell lines resulted in reduced cell growth and migration and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. 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 growth, survival, and migration in vitro, and tumor growth in vivo via inhibiting IGF-1 signaling in UM.