Penn Researchers Determine Structure of Binding
Site of Colon-Cancer Drug and Its Protein Target
Finding Will Steer Future Treatment Design
(Philadelphia, PA) - 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.
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
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.
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