GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE280nnn/GSE280280/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280280GEOGSEfalseReprogramming of Cellular Plasticity via ETS and MYC Core-regulatory circuits During Response to MAPK Inhibition in BRAF-mutant colorectal cancerBackground: Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC). BRAFV600E-mutated metastatic CRC may be a unique subtype, exhibiting a strong epigenetic phenotype. Interestingly, bromodomain 2, a reader protein for H3K27ac-marked enhancers, was found to be synthetically lethal in CRC with BRAF + EGFR inhibition. Design: We evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic CRC, followed by comprehensive profiling of transcriptomic and chromatin dynamics upon BET inhibitor combination treatment. Results: The combination of BET and standard MAPK inhibitors has demonstrated improved efficacy against BRAFV600E CRC and selective improvements against RAS-mutant CRC in vivo. We showed that BET + MAPK inhibition induced a profound downregulation of the MAPK signaling pathway compared to MAPK inhibition alone. The loss of activation signal on enhancers, as determined by H3K27ac, led to dysregulation of core-regulatory circuitries of CRC, especially loss of the auto-regulatory mechanism of the MAPK downstream E26 transformation–specific transcription factor family. Single nucleus multiome (RNA + ATAC) sequencing further distinguished differential transcriptomic and chromatin dynamics at cell type levels. Profound downregulation of well-differentiated cell types confirmed deep inhibition of MAPK signaling and downstream transcription factors. On the other hand, dedifferentiated cell populations were abundant after MAPK or combination inhibition, suggesting therapy-induced cell state switching and adaptation. Conclusion: We are evaluating BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAFV600E metastatic CRC. ClinicalTrial.gov identifier: NCT06102902.2026/04/24GSE280280GSM8593971GSM8593970GSM8593973GSM8593972GSM8593975GSM8593953GSM8593952GSM8593974GSM8593966GSM8593987GSM8593965GSM8593968GSM8593967GSM8593969GSM8593980GSM8593982GSM8593960GSM8593981GSM8593984GSM8593962GSM8593961GSM8593983GSM8593964GSM8593986GSM8593985GSM8593963GSM8593955GSM8593977GSM8593976GSM8593954GSM8593979GSM8593957GSM8593978GSM8593956GSM8593959GSM859395824676280280Homo sapiens