The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

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. 451Lu BRAFi-R and 1205Lu BRAFi-R cells were treated for 24 h with 5 μM PLX4032, 2.5 μM corin, 5 μM PLX4032 + 2.5 μM corin, or DMSO as a control. RNA was isolated from cells using an RNeasy Plus Mini kit (Qiagen Inc.) following the manufacturer's instructions. Paired-end RNA-Seq reads were quality- and adapter-trimmed using trimmomatic and gene expression was quantified using the salmon software package against the GENCODE v32 transcriptome summarized to the gene level. Differential expression analysis for pairwise cell type/treatment conditions was conducted using DESeq2 modeling counts as a function of treatment vs the relevant control.