In the United States and many other nations, melanoma is becoming increasingly more common. A major cause of melanoma is thought to be sun exposure; the ultraviolet radiation in sunlight can damage DNA and lead to cancer-causing genetic changes within skin cells.
In work published in the September issue of Nature Genetics, a team led by Yardena Samuels, Ph.D., of the National Human Genome Research Institute (NHGRI) sequenced the protein tyrosine kinase (PTK) gene family in tumor and blood samples from people with metastatic melanoma. The samples were collected by the study's coauthor Steven Rosenberg, M.D., Ph.D., a leading expert on melanoma and chief of surgery at the National Cancer Institute (NCI).
The PTK family includes many genes that, when mutated, promote various types of cancer. However, relatively little had been known about roles played by PTK genes in human melanoma. The NIH study was among the first to use large-scale DNA sequencing to systematically analyze all 86 members of the PTK gene family in melanoma samples.
The team's initial survey, which involved samples from 29 melanoma patients, identified mutations in functionally important regions of 19 PTK genes, only three of which had been previously implicated in melanoma. The researchers then conducted more detailed analyses of those 19 genes in samples from a total of 79 melanoma patients.
One of the newly implicated genes stood out from the rest. Researchers detected mutations in the ERBB4 gene (also known as HER4) in 19 percent of patients' tumors, making it by far the most frequently mutated PTK gene in melanoma. In addition, researchers found that many ERBB4 mutations were located in functionally important areas similar to those seen in other PTK oncogenes involved in lung cancer, brain cancer and gastric cancer.
Next, the researchers moved on to laboratory studies of melanoma cells with ERBB4 mutations. They found that these melanoma cells were dependent on the presence of mutant ERBB4 for their growth. What's more, the melanoma cells grew much more slowly when they were exposed to a chemotherapeutic drug known to inhibit ERBB4. The drug, called lapatinib (Tykerb), was approved by the Food and Drug Administration in 2007 for combination use in breast cancer patients already taking the drug capecitabine (Xeloda).
Encouraged by their study results, the researchers are planning a clinical trial using lapatinib in patients with metastatic melanoma harboring ERBB4 mutations. The clinical trial will be conducted under the direction of Dr. Rosenberg at the NIH Clinical Center.