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Inhibiting oncogenic BRAF signalling by copper depletion

Nature Reviews Cancer volume 14, pages 384–385 (2014)Cite this article

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Previous reports have shown that copper chelators effectively decrease the activity of the BRAF targets MEK1 and MEK2 (MEK1/2) kinases, which are key components of the oncogenic ERK pathway. Now, Brady et al. have shown that either decreasing levels of copper transporter 1 (CTR1) or mutating copper binding sites in MEK1 both decrease the activation of ERK1 and ERK2 (ERK1/2) in response to BRAF signalling and lead to decreased tumorigenesis in mice.

The authors then used targeted mutagenesis to show that mutations disrupting copper binding sites in MEK1 decreased ERK1/2 signalling in vitro and xenografts derived from MEFs carrying these mutated MEK1 proteins were significantly smaller. Conversely, they artificially engineered a MEK mutant whose activity was independent of copper by fusing the ERK-binding domain of MEK1 to the kinase domain of MEK5, which lacks two sites that are important for copper binding. This copper-independent MEK mutant restored ERK1/2 phosphorylation in Ctr1−/− MEFs, and xenografts derived from these cells showed increased tumorigenesis compared with those derived from Ctr1−/− MEFs.

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References

  1. Brady, D. C. et al. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature http://dx.doi.org/10.1038/nature13180 (2014)

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  1. Isabel Lokody
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Lokody, I. Inhibiting oncogenic BRAF signalling by copper depletion. Nat Rev Cancer 14, 384–385 (2014). https://doi.org/10.1038/nrc3745

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