AXL is a novel ERK5/KLF4 target in MEK inhibitor-treated melanoma - PubMed
6 hours ago
- #AXL Signaling
- #Melanoma
- #Therapy Resistance
- The RAS/RAF/MEK/ERK1/2 MAPK pathway is a key treatment target in advanced BRAF-mutated melanoma, often using BRAF and MEK inhibitors, but therapy resistance limits its effectiveness.
- NRAS-mutant melanomas lack targetable BRAF oncogenes and show poor response to MEK inhibitors, with compensatory activation of the MEK5/ERK5 pathway potentially driving resistance.
- In NRAS-mutant melanoma, MEK inhibitor exposure induces compensatory ERK5 activation and upregulates KLF2 and KLF4, but these factors were found dispensable for proliferative and anti-apoptotic effects in resistance.
- AXL, a receptor tyrosine kinase linked to metastasis and phenotypic switching, was identified as a critical ERK5/KLF4 target induced during MEK inhibitor resistance.
- Loss of KLF4 or depletion of AXL reduced melanoma cell migration and invasion, indicating KLF4's role in regulating invasiveness and the ERK5/KLF4/AXL axis in driving resistance and metastatic potential.
- Targeting the ERK5/KLF4/AXL signaling axis may improve MAPK-directed therapies and potentially enhance immune therapies in NRAS-mutant melanoma.