AXL is a novel ERK5/KLF4 target in MEKi-treated melanoma

Using siRNA and CRISPR/Cas9, we examined their contribution to MEKi resistance through functional assays and RNA sequencing. Surprisingly, KLF2 and KLF4 were dispensable for the proliferative and anti-apoptotic effects of compensatory ERK5 activation in MEKi-exposed melanoma. Instead, we identified AXL, a key receptor tyrosine kinase associated with metastasis and phenotypic switching, as critical ERK5/KLF4 target induced during MEKi resistance and demonstrate that KLF4 loss or AXL depletion results in reduced melanoma cell migration and invasion.

Our study describes a novel ERK5/KLF4/AXL signaling axis that drives MEKi resistance and metastatic potential in NRAS-mutant melanoma. Targeting this pathway may enhance the efficacy of MAPK-directed therapies and potentially improve responses to immune therapy, where AXL expression similarly promotes tumor progression.