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The University of Texas MD Anderson Cancer Center

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Clin. Cancer Res., May 08 2026, | https://doi.org/10.1158/1078-0432.CCR-25-4370 Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory Circuits During Response to MAPK Inhibition in BRAF-mutant Colorectal Cancer

Hey Min Lee ^1,2, Zhao Zheng³, Alexey Sorokin ¹, Chi Wut Wong ¹, Stefania Napolitano¹, Saikat Chowdhury ¹, Preeti Marie Kanikarla ¹, Anand K. Singh ³, Veena Kochat ³, Christopher A. Bristow ⁴, Sanjana Srinivasan ⁴, Michael Peoples ⁴, Emre Arslan ³, Jumanah Yousef Alshenaifi ^1,2, Oscar E.Villarreal ^1,2, Van K. Morris ¹, John Paul Shen¹, Funda Meric-Bernstam ⁵, Abhinav K Jain ⁶, NatalieWall Fowlkes ⁷, Amanda Anderson ⁷, David G Menter ¹, Ajay Kumar Saw ³, Kunal Rai ^{3 *}, and ScottKopetz^{1 *}

¹Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

²The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas, USA.

³Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ⁴Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

⁵Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

⁶Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

⁷Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

^*Corresponding authors: correspondence to Kunal Rai or ScottKopetz

Abstract

Purpose: Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC), particularly in the BRAF^V600E-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 CRC, followed by comprehensive transcriptomic and chromatin profiling.

Results: BET plus standard MAPK inhibitors demonstrated improved efficacy against BRAF^V600E CRC and selective improvements against RAS-mutant CRC in vivo. This combination induced a more profound downregulation of the MAPK signaling pathway than MAPK inhibition alone. The loss of activation signal on H3K27ac-marked enhancers led to the dysregulation of core-regulatory circuitries, especially the MAPK downstream E26 transformation-specific transcription factor family and MYC. Single-nucleus RNA+ATAC 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 transcription factors. Conversely, an abundance of dedifferentiated cell populations emerged after MAPK or combination inhibition, suggesting therapy-induced cell-state switching and adaptation.

Conclusion: Our work demonstrates that BET inhibition improves MAPK signaling blockade through profound epigenetic reprogramming of core transcription factor circuits. These findings provide a preclinical rationale for the evaluation of BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAF^V600Emetastatic CRC (NCT06102902).

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