The V600E mutation in BRAF kinase is associated with oncogenesis in melanoma and other cancers. BRAF V600E phosphorylates and activates MEK1 and MEK2 kinases, which phosphorylate and activate ERK1 and ERK2 kinases, resulting in activation of the MAPK pathway. The addition of a BRAF V600E inhibitor to a MEK1/2 inhibitor increases survival benefit in metastatic melanoma.
After previously finding that copper influx enhances MEK1 phosphorylation of ERK1/2 through a copper-MEK1 interaction, Brady and colleagues recently reported in Nature that both reduction of levels of copper transporter 1 (CTR1) and presence of MEK1 mutations that disrupt copper binding result in inhibition of BRAF V600E–driven signaling and tumorigenesis in mice and in human cells. Further, a MEK1-MEK5 chimera that phosphorylates ERK1/2 independently of copper and an active ERK2 both restored tumor growth of Ctr1-negative mouse cells. Treatment with copper chelators resulted in reduced tumor growth of human and mouse cells transformed by BRAF V600E or engineered to be resistant to BRAF inhibition.
The investigators concluded, “[T]hese results suggest that [copper]-chelation therapy could be repurposed to treat cancers containing the BRAF V600E mutation.” ■
Brady DC, et al: Nature. April 9, 2014 (early release online).
