Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer.
Elias Orouji, Ayush T Raman, Anand K Singh, Alexey Sorokin, Emre Arslan, Archit K Ghosh, Jonathan Schulz, Christopher Terranova, Shan Jiang, Ming Tang, Mayinuer Maitituoheti, Scot C Callahan, Praveen Barrodia, Katarzyna Tomczak, Yingda Jiang, Zhiqin Jiang, Jennifer S Davis, Sukhen Ghosh, Hey Min Lee, Laura Reyes-Uribe, Kyle Chang, Yusha Liu, Huiqin Chen, Ali Azhdarinia, Jeffrey Morris, Eduardo Vilar, Kendra S Carmon, Scott E Kopetz, Kunal Rai
Author Information
Elias Orouji: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ORCID
Ayush T Raman: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ORCID
Anand K Singh: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Alexey Sorokin: Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Emre Arslan: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ORCID
Archit K Ghosh: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Jonathan Schulz: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Christopher Terranova: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Shan Jiang: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Ming Tang: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mayinuer Maitituoheti: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Scot C Callahan: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Praveen Barrodia: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Katarzyna Tomczak: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Yingda Jiang: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Zhiqin Jiang: Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Jennifer S Davis: Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Sukhen Ghosh: Center for Translational Cancer Research, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Hey Min Lee: Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Laura Reyes-Uribe: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Kyle Chang: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Yusha Liu: University of Chicago Medical Center, Chicago, Illinois, USA.
Huiqin Chen: Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Ali Azhdarinia: Center for Translational Cancer Research, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Jeffrey Morris: University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Eduardo Vilar: MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. ORCID
Kendra S Carmon: MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Scott E Kopetz: Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Kunal Rai: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA krai@mdanderson.org. ORCID
OBJECTIVE: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described. DESIGN: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin. RESULTS: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as and was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups. CONCLUSION: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.
