GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE280nnn/GSE280266/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280266GEOGSEfalseReprogramming of Cellular Plasticity via ETS and MYC Core-regulatory circuits During Response to MAPK Inhibition in BRAF-mutant colorectal cancer.Background: 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: NCT06102902.2026/04/24GSE280266GSM8593391GSM8593390GSM8593393GSM8593392GSM8593395GSM8593394GSM8593397GSM8593396GSM8593377GSM8593399GSM8593410GSM8593398GSM8593376GSM8593412GSM8593379GSM8593378GSM8593411GSM8593414GSM8593413GSM8593405GSM8593404GSM8593407GSM8593406GSM8593409GSM8593408GSM8593380GSM8593382GSM8593381GSM8593384GSM8593383GSM8593386GSM8593385GSM8593421GSM8593388GSM8593420GSM8593387GSM8593423GSM8593401GSM8593389GSM8593400GSM8593422GSM8593403GSM8593402GSM8593416GSM8593415GSM8593418GSM8593417GSM859341924676280266Homo sapiens