GPCR-Gαq Signaling Drives Adaptive Resistance to MEK Inhibition in BRAF-Mutant Melanoma

Oncogenic BRAFV600E mutations drive constitutive MAPK signaling across various cancers; however, resistance to MEK inhibitors such as trametinib undermines clinical benefits, and the mechanisms sustaining MAPK activity under treatment remain unclear. We developed a lin-45(V627E) Caenorhabditis elegans model to mimic oncogenic BRAF signaling and found that these animals tolerate ultra-high doses of trametinib. This survival is driven by an adaptive resistance bypass, mediated by Gq-PLC{beta}-PKC signaling, which sustains MAPK activity despite MEK inhibition. Transcriptomic analyses of patient tumors and resistant melanoma cells reveal upregulation of the Gq subunits and GPCR PAR2 upon acquisition of resistance. Functional inhibition of PAR2 or downstream Gq signaling suppresses ERK reactivation, selectively impairs the viability of resistant cells. Furthermore, combined inhibition of MEK and Gq-PLC{beta}-PKC signaling synergistically suppresses tumor growth and restores trametinib sensitivity in xenograft models. These findings uncover adaptive GPCR-Gq-driven signaling rewiring as an evolutionarily conserved and therapeutically actionable vulnerability in MAPK-driven cancers.