Academic Journal
Reprogramming of Cellular Plasticity via ETS and MYC Core-Regulatory Circuits during Response to MAPK Inhibition in BRAF-Mutant Colorectal Cancer.
| Τίτλος: | Reprogramming of Cellular Plasticity via ETS and MYC Core-Regulatory Circuits during Response to MAPK Inhibition in BRAF-Mutant Colorectal Cancer. |
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| Συγγραφείς: | Lee HM; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas., Zheng Z; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Sorokin A; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wong CW; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Napolitano S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Chowdhury S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kanikarla Marie P; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Singh AK; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kochat V; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bristow CA; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas., Srinivasan S; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas., Peoples M; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas., Arslan E; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Alshenaifi JY; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas., Villarreal OE; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas., Morris VK; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Shen JP; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Meric-Bernstam F; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Jain AK; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas., Fowlkes NW; Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Anderson A; Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Menter DG; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Saw AK; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Rai K; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kopetz S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. |
| Πηγή: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2026 Aug 03; Vol. 32 (15), pp. 3309-3324. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Denville, NJ : American Association for Cancer Research, c1995- |
| Ιατρικοί όροι (MeSH): | Proto-Oncogene Proteins B-raf*/genetics , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/pathology , Colorectal Neoplasms*/metabolism , Proto-Oncogene Proteins c-myc*/genetics , Proto-Oncogene Proteins c-myc*/metabolism , Protein Kinase Inhibitors*/pharmacology , Cell Plasticity*/genetics , Cell Plasticity*/drug effects , Proto-Oncogene Proteins c-ets*/genetics , Proto-Oncogene Proteins c-ets*/metabolism , Mutation*, Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Animals ; Mice ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Epigenesis, Genetic |
| Περίληψη: | Purpose: Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer, particularly in the BRAFV600E-mutated metastatic subtype, which uniquely exhibits a strong epigenetic phenotype. Building on this epigenetic vulnerability, bromodomain 2, a reader of H3K27ac-marked enhancers, was found to be synthetically lethal with BRAF + EGFR inhibition. Experimental Design: We evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic colorectal cancer, followed by comprehensive transcriptomic and chromatin profiling. Results: BET plus standard MAPK inhibitors demonstrated improved efficacy against BRAFV600E colorectal cancer and selective improvements against RAS-mutant colorectal cancer in vivo. This combination induced a more profound downregulation of the MAPK signaling pathway than MAPK inhibition alone. The loss of activation signals on H3K27ac-marked enhancers led to the dysregulation of core regulatory circuitries, especially the MAPK downstream E26 transformation-specific transcription factor (TF) family and MYC. Single-nucleus RNA sequencing + Assay for Transposase-Accessible Chromatin using sequencing distinguished differential transcriptomic and chromatin dynamics at the cell-type level. Profound downregulation of well-differentiated cell types confirmed deep inhibition of MAPK signaling and downstream TF. Conversely, an abundance of dedifferentiated cell populations emerged after MAPK or combination inhibition, suggesting therapy-induced cell-state switching and adaptation. Conclusions: Our work demonstrates that BET inhibition improves MAPK signaling blockade through profound epigenetic reprogramming of core TF circuits. These findings provide a preclinical rationale for the evaluation of BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAFV600E metastatic colorectal cancer (NCT06102902). (©2026 American Association for Cancer Research.) |
| Σχόλια: | Update of: bioRxiv. 2025 Jun 20:2025.06.15.659716. doi: 10.1101/2025.06.15.659716.. (PMID: 40611889) |
| Grant Information: | CA016672 National Cancer Institute (NCI); 1S10OD024977-01 NIH Office of the Director (OD); RP210028 Cancer Prevention and Research Institute of Texas (CPRIT); P30CA016672 National Cancer Institute (NCI); P50CA221707 National Cancer Institute (NCI); CA230846 U.S. Department of Defense (DOD); RP200390 Cancer Prevention and Research Institute of Texas (CPRIT); RSG-19-187-01-DMC American Cancer Society (ACS) |
| Molecular Sequence: | ClinicalTrials.gov NCT06102902 |
| Substance Nomenclature: | EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) 0 (Proto-Oncogene Proteins c-myc) EC 2.7.11.1 (BRAF protein, human) 0 (Protein Kinase Inhibitors) 0 (Proto-Oncogene Proteins c-ets) 0 (MYC protein, human) |
| Entry Date(s): | Date Created: 20260508 Date Completed: 20260803 Latest Revision: 20260803 |
| Update Code: | 20260803 |
| DOI: | 10.1158/1078-0432.CCR-25-4370 |
| PMID: | 42101296 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-25-4370 |