Epigenetic Modification as a Therapeutic Target in BRAFV600E-mutated Metastatic Colorectal Cancer

Author

Hey Min LeeFollow

Author ORCID Identifier

0000-0001-7792-4226

Date of Graduation

5-2024

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Scott Kopetz, M.D., Ph.D.

Committee Member

Kunal Rai, Ph.D.

Committee Member

Robert C. Bast, M.D.

Committee Member

George A. Calin, Ph.D.

Committee Member

Anirban Maitra, M.B.B.S.

Committee Member

John Paul Y.C. Shen, M.D.

Abstract

Patients with BRAF^V600E-mutated metastatic colorectal cancer (mCRC) experience a worse prognosis and demonstrate only a 5% response rate to BRAF inhibitor treatment. In this study, adaptive resistance, and a potential combination of standard therapies in BRAF^V600E CRC were unveiled. Intriguingly, a robust association of BRAF^V600E mutation and DNA hypermethylation suggests this is a unique subgroup harboring aberrant epigenetic phenotype. Firstly, DNA methyltransferase (DNMT) inhibitor treatment induced profound DNA hypomethylation in vivo, but minimal change in gene expression due to adaptive elevation of the repressive histone methylation, H3K27me3, leading to compensatory suppression of key tumor suppressor genes, including Wnt pathway genes. EZH2 inhibitors targeting H3K27me3 additively sensitized DNMT inhibitors in BRAF^V600E CRC. Additionally, the combination of bromodomain and extra-terminal protein (BET) inhibition in vivo with standard MAPK-targeted therapies showed deeper inhibition of the MAPK signaling and improved efficacy. Enhancer blockade disrupted the regulation of core transcription factors (TFs) of CRC, including the ETS family, downstream of MAPK signaling. BET plus MAPK combination successfully depleted proliferative and less differentiated cell populations enriched with MAPK signaling associated TFs, suggesting treatment impact on epigenetic reprogramming. Overall, the novelty of the studies lies in revealing abnormal chromatin dynamics of BRAF^V600E CRC and the determination of optimal epigenetic therapeutic intervention in BRAF^V600E CRC patients. Based on the preclinical data, the combination of BET, BRAF, and EGFR inhibition will be assessed in patients with BRAF^V600E CRC (NCT06102902).

Keywords

colorectal cancer, BRAF, epigenetics, CIMP, methylation, DNMT, BET, enhancer, combination therapy