by ecancer reporter Janet Fricker

Lowering copper levels could prove a useful strategy for treating cancers possessing a common mutation in the BRAF oncogene, reports a US study in ‘Nature’¹.

In a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and some other cancers, BRAF kinase is mutated (typically Val 600RGlu, V600E), to induce an active oncogenic state.

BRAF V600E phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1and ERK2 kinases, thereby stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer.

Targeting MEK1/2, it has been reasoned, might offer a new approach to tackle cancer.

Already Chris Counter and colleagues, from Duke University Medical Center, USA, have demonstrated that copper influx enhances MEK1 phosphorylation of ERK1/2 through an interaction between copper and MEK1 interaction².

In the current study the team has gone further to investigate whether decreasing the levels of CTR1 (Cu transporter 1), or introducing mutations in MEK1 that disrupt binding to copper might prove a valuable approach.

For copper binding they utilised copper chelators used in the treatment of copper overload disorders, such as Wilson disease.

In mice and human cell settings they showed that decreasing levels of CTR1, or creating mutations in MEK1 that disrupt copper binding decreased BRAFV600E driven signalling and tumorigenesis.

Conversely, a MEK1–MEK5 chimera that phosphorylated ERK1/2 independently of copper restored tumour growth in murine cells lacking CTR1.

“Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAFV600E mutation,” write the authors, adding that copper chelators are generally safe and economical drugs that have been used by patients daily for decades to manage copper levels.

Reference

1. D Brady, M Crowe, M Turski, et al. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 

2. Turski M, D Brady, H Kim, et al. A novel role for copper in Ras/mitogen-activated protein kinase signaling. Mol. Cell. Bio 2012, 32, 1284–1295.