Clin Cancer Res: Combined inhibition of G alpha and MEK can significantly improve the therapeutic effect of grape membrane melanoma

All grape membrane melanomas and some other melanoma subsypes are driven by the activation of the G alphaq path.
Although we have come a long way in understanding the molecular understanding of the key driver signaling pathrapies in the pathogenesis of the disease, targeted treatment of these melanomas is still difficult.
G alphaq inhibitors have shown good preclinical results, but their therapeutic activity in different G alphaq mutation environments varied greatly.
Hitchman et al. used an isometrial melanin cell system to systematically detect hot mutations (e.g. GNAQ: G48V, R183Q, Q209L) and (CYSLTR2: L129Q) found in the human grape membrane melanoma GNAQ and CYSLTR2 genes.
the cell system and human grape membrane melanoma cell lines were used in heterogeneous transplantation studies to evaluate the therapeutic activity of single G alphaq inhibition and combined MEK inhibition.
results of YM-254890 inhibition of cell activity in different mutants prove that the G alphaq inhibitor YM-254890 inhibits downstream signals and cell growth in all mutants.
in the body, YM-254890 can slow tumor growth, but does not cause the human grape membrane melanoma transplant tumor to subside.
YM-254890 therapy can significantly reduce tumor volume through comprehensive transcription group analysis, the researchers observed that YM-254890 on the MAPK signal transduct path inhibition effect lasted 24 hours;
addition, the combined application of YM-254890 and MEK inhibitors can co-inhibit tumor growth and reduce tumor volume.
YM-254890 and MEK inhibitors combined to further reduce tumor volume in general, the results show that combined inhibition of G alphaq and MEK provides a promising treatment strategy for staphylococcal melanoma and expands the treatment time window for widely targeted G alphaq.