Data from 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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Abstract 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).

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