Researchers determine structure of binding site of colon-cancer drug Erbitux and its protein target

Researchers at the University of Pennsylvania School of Medicine have determined the precise molecular details of how Erbitux, a recently approved colorectal cancer drug, binds to its target on cancer cells. Knowing this chemical configuration will lead to better drug design for this family of cancer medications.

Colorectal cancer is one of the most frequently diagnosed cancers in men and women, as well as the second-leading cause of cancer-related death, according to the Centers for Disease Control and Prevention. Erbitux works by binding to a protein on the surface of cancer cells, thereby halting excessive cell growth that leads to tumors. Kate Ferguson, PhD, Assistant Professor of Physiology, and colleagues, describe their findings in the April cover article of Cancer Cell.

“By having determined the structure of Erbitux bound to its cellular target receptor, we get new insight into how the drug blocks the receptor’s cell growth-promoting activities, and can use this to guide future drug design,” says Ferguson.

As is characteristic of many epithelial cancers - such as cancers of the head and neck, breast, ovary, lung, and pancreas - the surface of cancer cells possess abnormally high levels of epidermal growth factor receptor (EGFR), the protein that interacts with Erbitux. (Click on thumbnail to view full-size image). These receptors are made up of three parts: one outside the cell; another passing through the cell membrane; and the third inside the cell. In a cancer cell, an extracellular hormone binds to the outer piece of EGFR, and causes the inside part to kick off a series of reactions that signal the cancerous cell to replicate and divide.

Ferguson and colleagues determined that Erbitux works to halt cell proliferation by blocking EGFR’s molecular doorway, disallowing hormones to bind and signal tumor growth. X-ray crystallography provided a snapshot of the interaction between Erbitux and the extracellular component of the cancer cell’s receptors.

The resulting structural information deciphered by Ferguson and colleagues emphasizes the importance of drug research targeting active protein receptors on cancer cells and tumors. As is the case in Erbitux, “the protein EGFR needs to not only be present on tumors but it needs to be there and be active,” says Ferguson.

“Understanding the structure could help us design alternatives to Erbitux that would be easier to deliver in small-molecule medications to be taken as a pill,” as opposed to the current intravenous administration of the drug, Ferguson adds. The researchers’ hope is that with these new insights into Erbitux’s action and structure, treatments for colorectal cancer and other epithelial cancers will be expanded, thereby contributing to the creation of future generations of improved cancer drugs.

The study was funded by the National Institutes of Health, the Burroughs Wellcome Fund, and ImClone Systems Inc. Study co-authors Paul Kussie and Jed. J.W. Wiltzius are employees of ImClone, the manufacturer of Erbitux. Shiqing Li and Karl R. Schmitz from Penn, and Philip D. Jeffrey (formerly from the Memorial Sloan-Kettering Cancer Center and now Princeton University) are also co-authors. The authors report no conflicts of interest related to this research.