Copper is required for oncogenic BRAF signalling and tumorigenesis

Tumorigenesis driven by the oncogene BRAFV600E is shown both to depend on the BRAF substrates MEK1/2 associating with copper, and to be sensitive to copper-chelating drugs, suggesting merit in testing such drugs for the treatment of BRAF mutation-positive cancers. A large proportion of melanomas and some other cancers harbour mutations in the BRAF gene, most of them at codon 600, causing constitutive activation of the MAPK (mitogen-activated protein kinase) pathway. Following the discovery that copper transport promotes MAPK signalling in Drosophila by binding to and activating the kinase MEK, Chris Counter and colleagues now show that oncogenic signalling by mutant BRAF requires copper binding to MEK, promoting activation of ERK1/2, the next kinases in the cascade. Interfering with copper availability by genetic means or with copper-chelating agents reduces BRAF-driven tumour growth in vivo in mouse models, and also of cancer cells that have become resistant to BRAF inhibitors. Thus copper chelators, already in the clinic for other indications, may prove useful for the treatment of BRAF-mutant tumours in combination with BRAF inhibitors, and potentially to prevent resistance. The BRAF kinase is mutated, typically Val 600→Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers1,2. BRAFV600Ephosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer3. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma4, an effect that is increased when administered together with a BRAFV600Einhibitor5. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu–MEK1 interaction6. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAFV600E-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1–MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease7decreased tumour growth of human or murine cells transformed by BRAFV600E or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAFV600Emutation.