A new study titled “PRMT1-mediated methylation of the EGF receptor regulates signalling and cetuximab response” may help explain why the human body sometimes becomes resistant to therapy with Cetuximab (Erbitux®), a monoclonal antibody therapy that inhibits the epidermal growth factor receptor (EGFR), a key therapy used in the treatment of metastatic colorectal cancer. When individuals become resistant to therapy, the cancer can recur, reducing patients’ overall survival rate. The study was conducted by a team of researchers from The University of Texas MD Anderson Cancer Center, and was recently published in the Journal of Clinical Investigation.
The study provides new insights into how fundamental proteins called EGFRs are regulated, leading to cancer treatment resistance. EGFR is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands.
“Our study investigated the role of extracellular methylation in EGFR signaling, and unexpectedly discovered new information about how EGFR renders cancer cells resistant to cetuximab antibody therapy,” said Mien Chie Hung, Ph.D., chair of Molecular and Cellular Oncology and study’s senior author, in a recent news release.
Methylation is a process through which proteins are chemically modified by the addition of a methyl group, and it can alter a protein’s function. When EGFR is abnormally expressed, it can cause cellular alterations including runaway cell growth, reduced cell death, the formation of tumours and metastasis. Interestingly, in the study, the research team found that the expression of methylation-defective EGFR reduced tumor growth in mice.
“More importantly, we showed that increased methylation of EGFR resulted in resistance to cetuximab mediated cancer cell growth,” explained Dr. Hung. “This correlated with poorer clinical outcomes observed in colorectal cancer patients and higher recurrence rates following cetuximab treatment.”
The results from the study revealed that methylation of EGFR was mediated by a protein called PRMT1 that is involved in a variety of processes, including gene transcription, DNA repair, and signal transduction.
“EGFR methylation sustained signaling activity and cell proliferation even in the presence of cetuximab,” said Dr. Hung. “This data suggests that this specific methylation plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.”