Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
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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Lee Hey Min, Zheng Zhao, Sorokin Alexey, Wong Chi Wut, Napolitano Stefania, Chowdhury Saikat, Kanikarla Marie Preeti, Singh Anand K, Kochat Veena, Bristow Christopher A, Srinivasan Sanjana, Peoples Michael, Arslan Emre, Alshenaifi Jumanah Yousef, Villarreal Oscar E, Morris Van K, Shen John Paul, Meric-Bernstam Funda, Jain Abhinav K, Fowlkes Natalie Wall, Anderson Amanda, Menter David G, Saw Ajay Kumar, Rai Kunal, Kopetz Scott
Аннотация
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).
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).