Copper’s Role In Cancer

In a variety of cancers, including many melanomas, several thyroid cancers, and hairy cell leukemia, a single mutation of a valine to a glutamic acid residue in the BRAF kinase protein activates a biological signal transduction pathway leading to tumor growth. Now, researchers led by Christopher M. Counter and Dennis J. Thiele of Duke University show that limiting access of these BRAF-related cancer cells to copper inhibits growth of tumors (Nature 2014, DOI: 10.1038/nature13180). In the first step of this process, the BRAF kinase phosphorylates a protein called MEK1. The team found that MEK1 requires copper in its active site to continue propagating cancer signals. Working with mice, they interfered with MEK1’s access to copper, either by using copper chelators or by mutating MEK1’s ability to bind copper, and discovered that tumor growth was inhibited. Several inexpensive copper chelators, including tetrathiomolybdate, d-penicillamine, and trientine, are already on the market to treat a copper-related genetic disorder called Wilson’s disease. The team proposes that copper chelation therapy could be repurposed to treat BRAF mutation cancers. This idea is now being tested in a clinical trial involving trientine.