Potent target for stopping colon cancer

UNC-CHAPEL HILL (US) — Scientists have found a drug target that kills colon cancers more effectively than current therapies. The finding could suggest a new path for developing powerful anti-cancer drugs.

Therapies that target the epidermal growth factor receptor, or EGFR, have been used for a number of cancers. But these drugs called EGFR inhibitors, such as cetuximab, have not been very successful against colon cancer.

Drugs that target the closely related receptor ERBB3 would probably be much more effective at treating most colorectal cancers, says the study’s lead author David Threadgill, an adjunct genetics professor at the University of North Carolina at Chapel Hill School of Medicine.

The researchers genetically blocked ERBB3 in a mouse model of colon cancer and in human colon cancer cell lines.

“If you genetically remove ERBB3, as you would if you were pharmacologically targeting it, then the mice rarely develop colon cancer,” adds Threadgill, who also is a member of the UNC Lineberger Comprehensive Cancer Center and a professor in the genetics department at North Carolina State University.

In the human colon cancer cell lines that are resistant to EGFR inhibitors, cell death increased dramatically when ERBB3 was genetically removed. “So ERBB3 is essential for preventing colon cancer cells from dying,” Threadgill explains.

Threadgill is testing a pharmacologic inhibitor to get the same anti-ERBB3 effect they achieved with genetics. “If we can use an inhibitor to block ERBB3, then it should be a very potent anti-cancer therapeutic,” he notes.

Many cancer therapeutics, such as EGFR inhibitors, target proteins that are kinases—enzymes that initiate a cascade of signals that tell cells to reproduce. But ERBB3 is a pseudo-kinase; it functions only by binding with other proteins that have kinase activity.

“This study shows that targets that historically hadn’t been considered because they don’t have the typical activities of a kinase can be equally if not more important in supporting cancer cells,” Threadgill adds.

Researchers from Ewha Womans University in Seoul (Republic of Korea) and the University of Texas M.D. Anderson Cancer Center contributed to the study, which was funded by the National Cancer Institute, the National Science Foundation, and the Korea Science and Engineering Foundation. Findings were published online August 17 in the Journal of Clinical Investigation.

UNC-Chapel Hill news: http://uncnews.unc.edu