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New research published in the Journal of Experimental & Clinical Cancer Research has identified a novel therapeutic strategy through which tumor resistance can be overcome to more effectively treat colorectal cancer. The third leading cause of cancer-related deaths in men and women in the United States, colorectal tumors are often capable of developing a resistance to some of the most common chemotherapies and targeted therapies used to treat the disease.

“Identifying the key vulnerability of drug-resistant colorectal cancer cells and developing therapeutic strategies targeting such vulnerability is critically important for more effective treatment of the disease,” said study corresponding author Yuesheng Zhang, M.D., Ph.D., the Harrigan, Haw, Luck Families Chair in Cancer Research and a member of the Developmental Therapeutics research program research program at VCU Massey Cancer Center, as well as a professor in the Department of Pharmacology and Toxicology at the VCU School of Medicine.

A class of targeted therapies known as epidermal growth factor receptor (EGFR) inhibitors have been clinically effective treatment options for colorectal cancer. More than 80% of colorectal tumors are EGFR-positive — with overexpression in more than half — and these drugs work by targeting the EGFR protein to hamper cancer cell growth. However, resistance to these therapies is common. The reason for this resistance is not scientifically well-known, making it difficult to develop more effective treatment strategies.

It was previously believed that resistance to EGFR inhibitors — examples of which include cetuximab and panitumumab — resulted from mutations in a series of cancer-related genes, such as KRAS, BRAF and PIK3CA. But Zhang’s research indicates this is not the case.

“Our research shows, unexpectedly, that colorectal cancer resistance to cetuximab and panitumumab results primarily from their inability to suppress EGFR,” Zhang said.

Essentially, the researchers determined that the drugs specifically designed to limit the function of EGFR were not as effective as previously thought.

Looking for alternative treatment methods, Zhang and his collaborators tested the use of a recombinant human protein therapy called PEPD-G278D in colorectal tumor cells and in mouse tumor models. They found that PEPD-G278D breaks down the activity of EGFR, along with its genetic family member and cancer-influencer HER2, by binding to the receptors on the outer membranes of colorectal cancer cells.

“PEPD-G278D strongly inhibits the growth of cancer cells and tumors overexpressing EGFR and/or HER2,” Zhang said, adding that PEPD-G278D only inhibited EGFR in cancer cells where there is an abundance of the protein, but not in regular cells where there is a normal level of EGFR.

Additionally, the researchers found that using an oral medication called aderbasib in combination with PEPD-G278D allowed for a more targeted reduction of tumor growth. Aderbasib by itself was not found to be effective in this study but it enhances target engagement by PEPD-G278D. The researchers also found that adding the widely used chemotherapy fluorouracil further enhanced the antitumor capabilities of PEPD.

“These findings suggest that a therapeutic strategy centered on PEPD-G278D is highly promising for overcoming drug resistance in colorectal cancer,” Zhang said. “It will be interesting to investigate whether other chemotherapeutic agents used in colorectal cancer treatment also enhance tumor inhibition when combined with the PEPD-based treatment.”

Zhang collaborated on this research with Lu Yang, Ph.D., assistant professor in the VCU Department of Pharmacology and Toxicology; and Arup Bhattacharya, Ph.D., Fengzhi Li, Ph.D., Yun Li, M.S., Xiang Ling, Ph.D., and Sandra Sexton, D.V.M., of Roswell Park Comprehensive Cancer Center.

This research was supported, in part, by the National Institutes of Health (R01CA215093, R01CA244601, P30CA016056 and S10OD16450) and Roswell Park Alliance Foundation.

Written by: Blake Belden