ANXA1-Derived Peptide Increases Melanoma Cell Sensitivity to Vemurafenib by Downregulating EphA2

Vemurafenib (VEM) is a BRAF inhibitor that improves the prognosis of melanoma, but acquired resistance represents a key limitation to its clinical efficacy. This study investigated the potential of A11, an Annexin A1 (ANXA1)-derived peptide, to enhance VEM efficacy in both VEM-sensitive and VEM-resistant melanoma cells. We evaluated the effects of A11 in melanoma through in vitro assays (including MTT, clonogenic survival, apoptosis, and cell cycle analysis) and in vivo xenograft models in nude mice. Furthermore, we mechanistically interrogated A11-mediated suppression of EphA2 expression and the downstream pS897-EphA2/AKT/ERK signalling pathway in resistant and parental cell lines via Western blotting and immunohistochemistry (IHC). Critically, our study demonstrates that A11 inhibits melanoma cell proliferation and reverses VEM resistance through EphA2 downregulation, consequently ablating this oncogenic pathway. This research highlights the promising application value of A11 in improving the efficacy of VEM treatment in melanoma, particularly in VEM-resistant melanoma.