Malignant melanoma is a type of cancer that originally develops in the pigmented cells of the body, which are known as melanocytes. Mostly found in the skin, melanocytes are also present in the eye and some other locations inside the body. The rate of occurrence of malignant melanoma of the skin has continued to increase over the last 30 years. While excess exposure to the sun, resulting in severe blistering sunburns, has been shown to be a clear risk factor for the later development of melanoma, much of the biology of this type of cancer remains unknown.
Newly Discovered Mutations Associated with Melanoma
A recent study published by scientists working at both the US National Human Genome Research Institute and the Johns Hopkins Kimmel Cancer Center (1), reported the identification of a significant percentage (roughly 20%) of melanomas having frequent mutations in an important cell surface signaling molecule known as erbB4 (also known as HER4). The erbB4 protein is what is known as a “receptor tyrosine kinase” or RTK. It is present in the surface membrane of cells and normally starts signaling only when it is stimulated by the presence of a series of very specific growth promoting proteins, also referred to as growth or trophic factors. The mutations that have been identified, when present in the protein, let erbB4 signal without being told to do so.
Cancer and Mutations in Growth Factor Receptors
It has been known for some time that mutations in several different growth factor receptors can be associated with the development of cancers. Of particular interest regarding the erbB4 protein, is that it is a member of a family of related growth factor receptors known as the epidermal growth factor (or EGF) receptor family. Many cancer cells have been found to carry mutations in the genes in this family of proteins. One of the better known series of mutations to occur in this family happens in the protein erbB2, otherwise known as HER2. Mutations and increased expression in this protein are commonly found in certain breast cancers and unfortunately when present are typically associated with a worse prognosis.
erbB4 Mutations and Sensitivity to Chemotherapy Drugs
The mutations that were identified in erbB4 in the melanoma samples were found, not surprisingly, to cause an unregulated increase in growth of the cells harboring these mutations. Quite interestingly, when tested on cells grown in a culture dish, an already approved chemotherapy agent showed high effectiveness in stopping the growth of the tumor cells. The compound, known as Lapatinib, commercially available under the names Tykerb or Tyverb, was shown to be highly effective in blocking the ability of the mutated receptor tyrosine kinase to signal cells to grow.
The inference from this study is that Lapatinib, already approved to treat certain forms of breast cancer, could be a useful new tool in the treatment of some forms of melanoma. This compound acts by blocking the growth stimulating signaling inside the cell that is caused by the mutated receptor tyrosine kinase. And just as interestingly, the chemotherapeutic agent had a limited effect on cells containing the normal, non-mutated form of the protein. Perhaps this will open a new avenue for treatment for certain forms of melanoma.
Learn more about melanoma at the US National Cancer Institute (NCI).
1 - Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P; NISC Comparative Sequencing Program, Rosenberg SA, Samuels Y. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet. 2009 Aug 30. [Epub ahead of print] PubMed PMID: 19718025.
 |
