HTR2B antagonists sensitize uveal melanoma cells to Gαq inhibitor YM-254890 in cell lines
In uveal melanoma cell lines, blocking the serotonin receptor HTR2B increased sensitivity to a Gαq inhibitor, although the antagonists alone had little to no inhibitory effect.
Jenna Aumiller and colleagues report in Science Signaling that Gq-coupled G protein–coupled receptors (GPCRs), including the serotonin receptor HTR2B, enhance oncogenic signaling of the mutant G protein subunit Gαq-Q209L in uveal melanoma cells science.org
Science Signalingscience.orgOpen source ↗. Antagonists of HTR2B increased the sensitivity of these cells to the Gαq-specific inhibitor YM-254890. The experiments were performed on cultured cells, not in patients.
Mutant Gαq and its receptors
Uveal melanoma (UM) is the most common intraocular malignancy in adults. More than 90% of patients carry Q209L or Q209P mutations in the Gαq and Gα11 proteins. Glutamine at position 209 of G protein α subunits is required to terminate signaling that GPCRs initiate through heterotrimeric G proteins.
Mutationally active Gα subunits have been thought to signal independently of GPCRs, although some may retain the ability to bind them. The authors found that Gq-coupled GPCRs, including HTR2B, enhanced the oncogenic signaling of Gαq-QL. According to the journal's summary of the work, stimulation of these receptors also promoted cell proliferation in a range of UM cell lines. The same summary notes that UM metastasizes in about 50% of patients and has no effective therapies.
HTR2B antagonists and YM-254890
HTR2B antagonists alone had little to no inhibitory effect on the cells science.org
Science Signalingscience.orgOpen source ↗. Combined with YM-254890, however, they increased the sensitivity of UM cells to the inhibitor, as measured by signaling, cell viability and proliferation assays.
In a further experiment, UM cells were treated with HTR2B antagonists and low concentrations of YM-254890. This shifted endogenous Gαq-QL/QP mutants into an inactive conformation to a greater extent than YM-254890 alone. The authors conclude that Gq-coupled GPCRs enhance the oncogenicity of mutationally active Gαq proteins, and that antagonism of HTR2B promotes an inactive state of Gαq-QL/QP and increases sensitivity to a Gαq inhibitor.
The summary published with the study states that Gαq inhibitors of this type are currently too toxic for use in patients. The results come from cell-based assays and do not establish an effect in animals or humans.
