Targeting sFRP1 with WAY-316606 Suppresses Proliferation, Migration, and Invasion in Metastatic Melanoma

Background/Objectives: Melanoma is a highly aggressive cancer with a strong metastatic potential, and therapeutic resistance remains a major clinical challenge despite advances in targeted therapies and immunotherapies. Secreted frizzled-related protein 1 (sFRP1) exhibits context-dependent roles in cancer; however, its function in metastatic melanoma remains poorly defined. This study investigated the role of sFRP1 in melanoma progression and evaluated the anti-tumor effects of the pharmacological compound WAY-316606. Methods: sFRP1 expression was quantified in metastatic melanoma cell lines, xenograft models, and TCGA datasets. The anti-tumor effects of WAY-316606 on cell viability, cell cycle progression, cell migration and invasion, and expression of extracellular matrix (ECM)-related genes were assessed using WST assays, flow cytometry, wound healing and transwell invasion assays, and quantitative real-time PCR, respectively. Results: sFRP1 expression was consistently elevated in metastatic melanoma cell lines, xenograft models, and TCGA datasets, and high sFRP1 expression was associated with poor overall survival. WAY-316606 selectively suppressed melanoma cell viability with minimal cytotoxic effects on non-tumorigenic cells, and induced G1 phase cell cycle arrest. Furthermore, WAY-316606 markedly impaired the migratory and invasive capacities of metastatic melanoma cells, accompanied by downregulation of key ECM remodeling and fibrosis-related genes, including VIM, CCN2, FN1, and TGFBI. sFRP1 knockdown partially phenocopied the anti-migratory and gene expression effects of WAY-316606. Conclusions: Collectively, our findings identify sFRP1-asscoaited signaling contribute to aggressive melanoma phenotypes and highlight the therapeutic potential of its pharmacological inhibition using WAY-316606.