Conserved Gαq-PLCβ-PKC signaling mediates trametinib resistance in BRAF^V600E melanoma

Oncogenic mutations in BRAF, most commonly V600E, drive constitutive activation of the MAPK pathway in ~50% of melanomas. While MEK inhibitors such as trametinib, alone or in combination with BRAF inhibitors, are clinically effective, their therapeutic effects are restricted due to the development of drug resistance. Here we establish a Caenorhabditis elegans model carrying the oncogenic lin-45(V627E) allele, functionally equivalent to human BRAF^V600E, to investigate mechanisms of trametinib resistance. Genetic suppressor screening and transcriptomic profiling reveal that the EGL-30/Gαq-PLCβ-PKC axis promotes resistance by sustaining MAPK activity under MEK blockade. Pharmacological inhibition of PLCβ or PKC synergizes with trametinib to abolish MAPK signaling and restore drug sensitivity in worms. Importantly, this resistance mechanism is conserved in human melanoma: combined MEK and Gαq-PLCβ-PKC inhibition markedly enhances trametinib efficacy in BRAF^V600E melanoma cells and xenografts, and reverses acquired resistance in trametinib-resistant melanoma sublines. Together, our results identify a conserved Gαq-PLCβ-PKC pathway as a driver of trametinib resistance and provide preclinical evidence for its co-targeting with MEK inhibition as a therapeutic strategy in BRAF^V600E melanoma.