By studying G protein–coupled receptor (GPCR) signaling in various uveal melanoma cell lines, researchers led by Jenna Aumiller have found a way to make these cells more sensitive to compounds that inhibit cancer-linked signaling pathways. The study was published in „Science Signaling“ (DOI: 10.1126/scisignal.aeg1191). Uveal melanoma is a malignancy of the eye that metastasizes in about 50 percent of patients and has no effective therapies.
Almost all cases of uveal melanoma are driven by oncogenic G protein ?-subunit mutants such as G?q-Q209L/P, which are thought to stimulate proliferative, pro-tumorigenic signaling independently of their upstream GPCRs. Aumiller and colleagues now provide evidence that these oncogenic G proteins are more connected to their upstream receptors than previously thought. In a range of uveal melanoma cell lines, they found that stimulation of Gq-coupled GPCRs, including the serotonin receptor HTR2B, enhanced the oncogenic signaling of G?q-Q209L/P and promoted cellular proliferation.
Although blocking HTR2B signaling alone had no substantial effect on the proliferation of uveal melanoma cells, HTR2B antagonists rendered the cells sensitive to pharmacological inhibitors of G?q-Q209L/P, in part by inducing G?q-Q209L/P to adopt an inactive conformation. Currently, these G?q-Q209L/P inhibitors are too toxic to be used in patients. However, the data suggest that oncogenic mutant G protein ?-subunits retain the ability to interact with and be regulated by GPCRs, and that future therapeutic strategies involving inhibition of G?q-Q209L/P signaling in uveal melanoma should consider combined targeting of HTR2B.
