Fig. 1.

Mechanisms of resistance to BRAF-targeted therapy. V600E and KIAA1549-BRAF fusion lead to constitutive activation of MAPK signaling in tumor cells. MAPK phosphorylates downstream nuclear effectors that ultimately enhance cell survival and proliferation. One recognized mechanism of resistance to BRAF inhibition is the upregulation of CRAF, which activates MAPK through MEK. Concurrent inhibition of MEK overcomes this resistance. Both RAF and MEK inhibition, as well as EGFR gain-of-function mutation contribute to amplification of the PI3K/AKT/mTOR pathway that represents another mechanism of resistance to BRAF-targeted therapy. EGF epidermal growth factor, EGFR epidermal growth factor receptor, MAPK mitogen-activated protein kinase, MEK MAPK kinase, mTOR mammalian target of rapamycin, PI3K phosphoinositide 3-kinase, RAS rat sarcoma protein