An Unholy Alliance: Cooperation between BRAF and NF1 in Melanoma Development and BRAF Inhibitor Resistance

The putative role of NF1 loss in melanoma development and BRAF inhibitor resistance. A, loss of NF1 cooperates with mutant BRAF by increasing PI3K/AKT signaling and preventing entry into OIS. B, in normal cells NF1 suppresses RAS signaling by increasing its accumulation in the Ras-GDP (inactive state). C, when NF1 function is lost, Ras signaling increases and limits the response of BRAF-mutant melanoma cells to the BRAF inhibitor PLX4720 by increasing CRAF and PI3K/AKT signaling. BRAF-mutant/NF1-null cells/tumors show sensitivity to the pan-RAF inhibitor AZ628, the extracellular signal–regulated kinase (ERK) inhibitor VTX11e, and the combination of a MAP–ERK kinase (MEK) + mTOR inhibitor (PD0325901 and rapamycin).