Researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), have found that inhibition of the same protein produces different effects in mouse cell lines depending on whether those cell lines express normal or cancerous forms of Kit, a cell surface receptor critical for the development of some kinds of blood cells. These findings, appearing in the journal Blood online *, November 2004, reveal a potential new target for treating certain blood cell disorders.

A specific mutation affecting the catalytic domain of the Kit receptor results in a cancerous form of Kit found in patients with mast cell disease and some forms of acute myeloid leukemia. This particular Kit mutant, known as D814Y, is resistant to Gleevec™, a drug used to treat a variety of diseases associated with Kit and related proteins. Other types of cancer, including gastrointestinal stromal cell tumors, have different Kit mutations that are sensitive to Gleevec. One potential way to circumvent the Gleevec-resistant form of Kit is to target one or more of the proteins that are activated by Kit.

NCI researchers Diana Linnekin, Ph.D., and Tanya Jelacic, Ph.D., found that inhibition of one such Kit-activated protein, PKCδ (PKCdelta) (a member of a family of protein kinases involved in cell signaling), reduced the growth of a mouse mast cell line expressing the D814Y mutant Kit by approximately 40 percent. In contrast, PKCδ (PKCdelta) inhibition did not suppress the growth of normal mast cells. "This is the first demonstration of a function change in PKCδ (PKCdelta) resulting from a cancerous mutation in a growth factor receptor," said Linnekin.

Because anti-PKCδ (PKCdelta) drugs would specifically inhibit the growth of mutated cells and not affect normal ones, these results suggest that PKCδ (PKCdelta) may be a therapeutic target for mast cell disease associated with the D814Y mutation in Kit and possibly for other disorders associated with Kit catalytic domain mutations. "This work is a promising study on cancer inhibition," said Linnekin. "Dr. Jelacic and I believe that follow-up work with human cell lines, as well as work in mouse models of cancer, would be definitely worthwhile."

For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).