SRP487096 PRJNA1071542 GSE254701 The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma [ChIP-seq] Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated to date. Here, we evaluate the CoREST repressor complex and the recently developed bivalent inhibitor, corin, within the context of melanoma phenotype plasticity and therapeutic resistance. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin reveals specific effects on histone marks connected to EMT-associated transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin promotes resensitization to BRAFi therapy. DUSP1 is consistently downregulated in BRAFi-resistant melanomas which is reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity can be recapitulated by the p38 MAPK inhibitor, BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAFi- resistant melanoma. Overall design: 451Lu-R or 1205Lu-R melanoma cells were treated with 2.5 uM corin or DMSO for 24 h and grown to 80% confluency in 150 cm² plates. ChIP was conducted as previously described. The following antibodies were used for IP: H3K27ac (ab4729; lot GR3442884-1), H3K9ac (ab32129; lot GR3359686), or H3K4me2 (ab32356; lot GR3422075-2), with input samples as controls. Two biological replicates were performed for each cell line. Library prep and Illumina sequencing of ChIP DNA was performed by Azenta (Indianapolis, IN) with 40 million 2x150 bp paired-end reads for each sample. GSE254701 pubmed 38300709 parent_bioproject PRJNA1071546