Functional characterization of uveal melanoma oncogenes

Uveal melanoma (UM) is a currently untreatable form of melanoma with a 50% mortality rate. Characterization of the essential signaling pathways driving this cancer is critical to develop target therapies. Activating mutations in the G alpha q signaling pathway at the level of GNAQ, GNA11, or rarely CYSLTR2 or PLC beta 4 are considered alterations driving proliferation in UM and several other neoplastic disorders. Here, we systematically examined the oncogenic signaling output of various mutations recurrently identified in human tumors. We demonstrate that CYSLTR2 -> GNAQ/11 -> PLC beta act in a linear signaling cascade that, via protein kinase C (PKC), activates in parallel the MAP-kinase and FAK/Yes-associated protein pathways. Using genetic ablation and pharmacological inhibition, we show that the PKC/RasGRP3/MAPK signaling branch is the essential component that drives the proliferation of UM. Only inhibition of the MAPK branch but not the FAK branch synergizes with inhibition of the proximal cascade, providing a blueprint for combination therapy. All oncogenic signaling could be extinguished by the novel GNAQ/11 inhibitor YM-254890, in all UM cells with driver mutation in the G alpha q subunit or the upstream receptor. Our findings highlight the GNAQ/11 -> PLC beta -> PKC -> MAPK pathway as the central signaling axis to be suppressed pharmacologically to treat for neoplastic disorders with G alpha q pathway mutations.

Automated summary

The study identified the CYSLTR2 -> GNAQ/11 -> PLC beta signaling pathway as a key driver of uveal melanoma proliferation, with the PKC/RasGRP3/MAPK signaling branch being essential. Inhibition of the MAPK branch, but not the FAK branch, synergized with inhibition of the proximal cascade, providing a blueprint for combination therapy. All oncogenic signaling could be suppressed by the GNAQ/11 inhibitor YM-254890, highlighting its potential for treating neoplastic disorders with G alpha q pathway mutations.