{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE280nnn/GSE280266/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280266"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory circuits During Response to MAPK Inhibition in BRAF-mutant colorectal cancer.","description":"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.","dates":{"publication":"2026/04/24"},"accession":"GSE280266","cross_references":{"GSM":["GSM8593391","GSM8593390","GSM8593393","GSM8593392","GSM8593395","GSM8593394","GSM8593397","GSM8593396","GSM8593377","GSM8593399","GSM8593410","GSM8593398","GSM8593376","GSM8593379","GSM8593412","GSM8593378","GSM8593411","GSM8593414","GSM8593413","GSM8593405","GSM8593404","GSM8593407","GSM8593406","GSM8593409","GSM8593408","GSM8593380","GSM8593382","GSM8593381","GSM8593384","GSM8593383","GSM8593386","GSM8593385","GSM8593421","GSM8593388","GSM8593420","GSM8593387","GSM8593423","GSM8593401","GSM8593389","GSM8593400","GSM8593422","GSM8593403","GSM8593402","GSM8593416","GSM8593415","GSM8593418","GSM8593417","GSM8593419"],"GPL":["24676"],"GSE":["280266"],"taxon":["Homo sapiens"]}}