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

ABSTRACT: 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

SUBMITTER: Ke J 

PROVIDER: S-EPMC12667813 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature