GEO series
Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory circuits During Response to MAPK Inhibition in BRAF-mutant colorectal cancer
GSE280280
Homo sapiens
Genome binding/occupancy profiling by high throughput sequencing
36 samples
Submitted 2026/04/24
Platform GPL24676
Summary
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.
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE280280_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 36 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1177515 and SRA study SRP540717. Searching any of these in the dataset finder brings you back here.
Study design
36 conditions, each sampled once — no replicated groups
Read from 36 sample titles: 36 distinct titles with little repetition. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8593952 C5002; combo 2; BRD2; ChIP
- GSM8593953 C5002; combo 2; BRD4; ChIP
- GSM8593954 C5002; combo 2; Input; ChIP
- GSM8593955 C5002; combo 3; BRD2; ChIP
- GSM8593956 C5002; combo 3; BRD4; ChIP
- GSM8593957 C5002; combo 3; Input; ChIP
- GSM8593958 C5002; control 1; BRD2; ChIP
- GSM8593959 C5002; control 1; BRD4; ChIP
- GSM8593960 C5002; control 1; Input; ChIP
- GSM8593961 C5002; control 2; BRD2; ChIP
- GSM8593962 C5002; control 2; BRD4; ChIP
- GSM8593963 C5002; control 2; Input; ChIP
- GSM8593964 C5002; control 3; BRD2; ChIP
- GSM8593965 C5002; control 3; BRD4; ChIP
- GSM8593966 C5002; control 3; Input; ChIP
- GSM8593967 C5002; encorafenib+cetuximab 1; BRD2; ChIP
- GSM8593968 C5002; encorafenib+cetuximab 1; BRD4; ChIP
- GSM8593969 C5002; encorafenib+cetuximab 1; Input; ChIP
- GSM8593970 C5002; encorafenib+cetuximab 2; BRD2; ChIP
- GSM8593971 C5002; encorafenib+cetuximab 2; BRD4; ChIP
- GSM8593972 C5002; encorafenib+cetuximab 2; Input; ChIP
- GSM8593973 C5002; encorafenib+cetuximab 3; BRD2; ChIP
- GSM8593974 C5002; encorafenib+cetuximab 4; BRD4; ChIP
- GSM8593975 C5002; encorafenib+cetuximab 5; Input; ChIP
- GSM8593976 C5002; zen3694 1; BRD2; ChIP
- GSM8593977 C5002; zen3694 1; BRD4; ChIP
- GSM8593978 C5002; zen3694 1; Input; ChIP
- GSM8593979 C5002; zen3694 2; BRD2; ChIP
- GSM8593980 C5002; zen3694 2; BRD4; ChIP
- GSM8593981 C5002; zen3694 2; Input; ChIP
- GSM8593982 C5002; zen3694 3; BRD2; ChIP
- GSM8593983 C5002; zen3694 3; BRD4; ChIP
- GSM8593984 C5002; zen3694 3; Input; ChIP
- GSM8593985 C5002; combo 1; BRD2; ChIP
- GSM8593986 C5002; combo 1; BRD4; ChIP
- GSM8593987 C5002; combo 1; Input; ChIP
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