Dynamic cellular heterogeneity underlies melanoma progression and therapy resistance.,Advances in single-cell technologies have revealed an increasing number of tumor and microenvironment cell states in melanoma, but little is understood about their function in vivo.,Zebrafish models are a powerful system for discovery, live imaging, and functional investigation of cell states throughout melanoma progression and treatment.,By capturing dynamic melanoma states in living animals, zebrafish have the potential to resolve the complexity of melanoma heterogeneity from a single cell through disease processes within the context of the whole body, revealing novel cancer biology and therapeutic targets.
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.