RUNX2, a master osteogenic transcript ion factor, is overexpressed in several cancer cells; in melanoma it promotes cells migration and invasion as well as neoangiogenesis.,The annual mortality rates related to metastatic melanoma are high and novel agents are needed to improve melanoma patients’ survival.,It has been shown that lectins specifically target malignant cells since they present the Thomsen-Friedenreich antigen.,This disaccharide is hidden in normal cells, while it allows selective lectins binding in transformed cells.,Recently, an edible lectin named BEL β-trefoil has been obtained from the wild mushroom Boletus edulis.,Our previous study showed BEL β-trefoil effects on transcription factor RUNX2 downregulation as well as on the migration ability in melanoma cells treated in vitro.,Therefore, to better understand the role of this lectin, we investigated the BEL β-trefoil effects in a zebrafish in vivo model, transplanted with human melanoma cells expressing RUNX2.,Our data showed that BEL β-trefoil is able to spread in the tissues and to reduce the formation of metastases in melanoma xenotransplanted zebrafish.,In conclusion, BEL β-trefoil can be considered an effective biomolecule to counteract melanoma disease.
BRAF-mutant melanoma patients respond to BRAF inhibitors and MEK inhibitors (BRAFi/MEKi), but drug-tolerant cells persist, which may seed disease progression.,Adaptive activation of receptor tyrosine kinases (RTKs) has been associated with melanoma cell drug tolerance following targeted therapy.,While co-targeting individual RTKs can enhance the efficacy of BRAFi/MEKi effects, it remains unclear how to broadly target multiple RTKs to achieve more durable tumour growth inhibition.,The blockage of adaptive RTK responses by the new BET inhibitor (BETi), PLX51107, was measured by RPPA and Western blot.,Melanoma growth was evaluated in vitro by colony assay and EdU staining, as well as in skin reconstructs, xenografts and PDX models following BRAFi, MEKi and/or PLX51107 treatment.,Treatment with PLX51107 limited BRAFi/MEKi upregulation of ErbB3 and PDGFR-β expression levels.,Similar effects were observed following BRD2/4 depletion.,In stage III melanoma patients, expression of BRD2/4 was strongly correlated with ErbB3.,PLX51107 enhanced the effects of BRAFi/MEKi on inhibiting melanoma growth in vitro, in human skin reconstructs and in xenografts in vivo.,Continuous triple drug combination treatment resulted in significant weight loss in mice, but intermittent BETi combined with continuous BRAFi/MEKi treatment was tolerable and improved durable tumour inhibition outcomes.,Together, our data suggest that intermittent inhibition of BET proteins may improve the duration of responses following BRAFi/MEKi treatment in BRAF-mutant melanoma.