RAF1 and cancer: In Ras-mutated cancer cells or RAFi-resistant cancer cells with active Ras, CRAF is the key isoform of RAF family kinases responsible for disease progression and drug resistance [27, 32, 275–278], whose phosphorylation on the C-terminal 14-3-3 binding site by AMPK plays a determinant role in the paradoxical effect of RAF inhibitors, and AMPKi sensitizes these cancer cells to RAF inhibitors both in vitro and in vivo [231] (Wang & Hu, unpublished data) (Fig. 4b).