IGF1R Inhibition Enhances the Therapeutic Effects of Gq/11 Inhibition in Metastatic Uveal Melanoma Progression

Uveal melanoma (UM) is the most common intraocular tumor in adults, and up to 50% of patients develop metastatic disease, which remains uncurable. Because patients with metastatic UM have an average survival of less than 1 year after diagnosis, there is an urgent need to develop new treatment strategies. Although activating muta-tions in Gaq or Ga11 proteins are major drivers of pathogenesis, the therapeutic intervention of downstream Gaq/11targets has been unsuccessful in treating UM, possibly due to alternative signaling pathways and/or resistance mechanisms. Activation of the insulin -like growth factor 1 (IGF1) signaling pathway promotes cell growth, metastasis, and drug resistance in many types of cancers, including UM, where expression of the IGF1 receptor (IGF1R) correlates with a poor prognosis. In this article, we show that direct inhibition of Gaq/11 by the cyclic depsipeptide YM-254890 in combination with inhibition of IGF1R by linsitinib cooperatively inhibits downstream signaling and proliferation of UM cells. We further demonstrate that a 2-week combination treatment of 0.3 to 0.4 mg/kg of YM-254890 admin-istered by intraperitoneal injection and 25 to 40 mg/kg linsitinib administered by oral gavage effectively inhibits the growth of metastatic UM tumors in immunodeficient NOD scid gamma (NSG) mice and identifies the IGF1 pathway as a potential resistance mechanism in response to Gaq/11inhibition in UM. These data suggest that the combination of Gaq/11and IGF1R inhibition provides a promising therapeutic strategy to treat metastatic UM.