Colorectal Cancer Resistance to Treatment May Have Molecular Cause

Colorectal Cancer Resistance to Treatment May Have Molecular Cause

University of Texas MD Anderson Cancer Center researchers have linked epidermal growth factor receptor regulation to colorectal cancer tumorigenesis, poor patient outcomes, and resistance to treatment with cetuximab (Erbitux). The study, titled “PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response,” was published in The Journal of Clinical Investigation.

Treatment of metastatic colorectal cancer (mCRC) with monoclonal antibody anti-epidermal growth factor receptor (EGFR) medicines, such as cetuximab (Erbitux), is one of the main strategies used in the clinic. However, despite the considerable potential of EGFR-targeted monoclonal antibodies therapies, some patients do not respond to treatment and the cancer recurs and becomes resistant. To understand this outcome, researchers studied the mechanisms of EGFR regulation, particularly the role of extracellular methylation in EGFR signaling in cancer cell resistance to cetuximab.

Methylation is a process that chemically alters proteins and regulates their function, and that upon aberrant performance can lead to protein dysfunction and overexpression, resulting in exaggerated cell growth, lower cell death and tumor formation, and metastasis.

Researchers showed that methylation of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to the growth factor, leading to gene transcription and signaling activation. Furthermore, increased methylation of EGFR maintained signaling activation and cell proliferation in the presence of cetuximab, leading researchers to establish a positive correlation between increased methylation and resistance to this cancer therapy. Importantly, enhanced EGFR methylation also correlated with poorer patient outcomes and higher recurrence rates in colorectal cancer patients.

Dr. Mien Chie Hung, PhD, chair of Molecular and Cellular Oncology, said in a press release, “EGFR methylation sustained signaling activity and cell proliferation even in the presence of cetuximab. This data suggests that this specific methylation plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.”

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