Uveal Melanoma Crosstalk May Guide Targeted Therapies

By studying G protein–coupled receptor (GPCR) signaling in a range of uveal melanoma cell lines, Jenna Aumiller and colleagues have discovered a way to make these cells more sensitive to compounds that inhibit cancer-linked (or oncogenic) signaling pathways. Uveal melanoma (UM) is a malignancy of the eye that metastasizes in about 50% of patients and has no effective therapies. Almost all cases of UM are driven by oncogenic G protein α-subunit mutants, such as Gα_q-Q209L/P, which are thought to stimulate proliferative, pro-tumorigenic signaling independently of their upstream GPCRs. However, Aumiller et al. now provide evidence that that these oncogenic G proteins are more connected to their upstream receptors than previously thought. In a range of UM cell lines, the authors found that stimulation of Gq-coupled GPCRs, including the serotonin receptor HTR2B, enhanced the oncogenic signaling of Gα_q-Q209L/P and promoted cellular proliferation. Although blocking HTR2B signaling alone had no substantial effect on the proliferation of UM cells, HTR2B antagonists rendered the UM cells sensitive to pharmacological inhibitors of Gα_q-Q209L/P, in part by inducing Gα_q-Q209L/P to adopt an inactive conformation. Currently, these Gα_q-Q209L/P inhibitors are too toxic to be used in patients. However, these data suggest that oncogenic mutant G protein α-subunits retain the ability to interact with, and be regulated by, GPCRs, and that future therapeutic strategies that involve inhibiting Gα_q-Q209L/P signaling in UM should consider the combined targeting of HTR2B.