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. Since metastatic UM patients have an average survival of less than 1 year after diagnosis, there is an urgent need to develop new treatment strategies. While activating mutations in Galphaq or Galpha11 proteins are major drivers of pathogenesis, therapeutic intervention of downstream Galphaq/11 targets 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. Here we show that direct inhibition of Galphaq/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 0.3-0.4 mg/kg of YM-254890 administered by intraperitoneal injection and 25-40 mg/kg linsitinib administered by oral gavage effectively inhibits the growth of metastatic UM tumors in immunodeficient NOD scid gamma (NSG) mice and identify the IGF1 pathway as a potential resistance mechanism in response to Galphaq/11 inhibition in UM. These data suggest that the combination of Galphaq/11 and IGF1R inhibition provides a promising therapeutic strategy to treating metastatic UM.