Inhibition of RAF alone or in combination with MEK is effective in slowing the progression of BRAF V600-mutanted cancers. However, tumors adapt to therapy and drug effectiveness is limited by resistance which is associated with RAS mutations, BRAF V600E splice variants, BRAF amplification and MEK mutations. Additionally, stromal cells in the tumor microenvironment release hepatocyte growth factor/cytokines could promote resistance to RAF inhibitors and reactivate ERK signaling pathway by activating PI3K signaling.