Activation of the RAS-RAF-MEK-ERK signaling pathway in resistant tumors can also be caused by activating mutations in Nras, Mek1, or Mek2. Notably, the finding of activating Nras mutations with concurrent Braf mutations in these post-BRAFi tumors contrasts with the mutual exclusivity seen between these mutations in treatment-naïve melanomas,6 and thus reflects the profound effect this targeted therapy has on disease biology. This evidence concerns the gene BRAF and melanoma.