Uveal melanoma (UM) is an aggressive cancer that originates from melanocytes within the uveal tract of the eye and up to 50% of UM patients develop metastatic disease. The median overall survival after metastasis is only 10.2 months with a 1-year survival rate of 43%. Mutations in the GNAQ and GNA11 (GNAQ/11) genes have been identified in 85-95% of UM. These mutations induce the activation of the downstream effector protein kinase C (PKC) and constitutive signaling of the mitogen activated protein kinase (MAPK) pathway. Therapies targeting PKC such as the PKC inhibitor IDE196 showed limited anti-tumour activity in a Phase I clinical trial for metastatic UM,with an objective response rate of 9.1%and a median duration of response of only 10.15 months. In this study, we extended previous work showing that PKC inhibition did not suppress the PI3K/AKT/mTOR cascade in UM. In order to understand the contribution of PI3K signaling in PKC inhibitor responses, we treated a panel of UM cell models with PKC inhibitor IDE196 and the PI3K/mTOR inhibitor BEZ235. Six UM cell lines, including 4 GNAQ/11-mutant (GNAQ/11-mt) and 2 GNAQ-wild type (GNAQ-wt) cell lines, were treated with IDE196 ± BEZ325 for 72h and cell survival was assessed using propidium iodide-based flow cytometry. Cell cycle analyses showed a 2 to 11-fold increase and drug synergy in cell death in the GNAQ/11-mt cells treated with combination IDE196+BEZ235 compared to monotherapies. Both GNAQ/11-wt UM cell lines were resistant to combination therapies with minimal cell death. Drug synergy was associated with more potent inhibition of the MAPK and PI3K pathways, as determined by the pronounced inhibition of S6 phosphorylation, detected by immunoblotting 24h after treatment with the combination compared to either drug alone. These data confirm that PKC inhibition is not sufficient to suppress the PI3K/AKT/mTOR survival pathway in UM, and that dual inhibition of the PKC and PI3K pathways synergises to induce cell death in UM. This work provides opportunities for new therapeutic combinations that may be effective in the treatment of metastatic UM.