Cupric Needs: Copper Is Necessary for Oncogenic BRAF Signaling

Kenneth Y. Tsai, MD, PhD 

Copper-chelation therapy could be used to treat cancers containing the BRAFV600E mutation.

Metal cations are essential co-factors for many enzymes. Genetic evidence in flies showed the importance of copper in ERK kinase signaling. Brady and colleagues took this research a step further by focusing on how copper contributes to signaling in mutant BRAF cancers, including melanoma. In melanoma, BRAFV600E activates the MEK1 and MEK2 kinases, which in turn activate the ERK1 and ERK2 kinases, which stimulate the MAPK pathway and promote cancer. Disrupting BRAF or MEK signaling shuts this pathway off, resulting in clinical responses.

Using mice lacking the Ctr1 copper transporter, they showed that BRAFV600E signaling to ERK is dependent on intact copper transport, because MEK requires copper for activity. Proliferation of melanoma cell lines dependent upon BRAFV600E also require Ctr1, and BRAFV600E-driven lung cancer development was suppressed in mice lacking Ctr1. Multiple copper chelators, including tetrathiomolybdate (TTM), are used to ameliorate copper overload in Wilson disease. Application of TTM and a low copper diet in mice partially inhibited BRAFV600E-driven tumors, including tumors that had been rendered resistant to vemurafenib.

Citation(s):

Brady DC et al. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 2014 Apr 9; [e-pub ahead of print].