The multikinase inhibitor sorafenib is under clinical investigation for the 
treatment of many solid tumors, but in most cases, the molecular target 
responsible for the clinical effect is unknown. Furthermore, enhancing the 
effectiveness of sorafenib using combination strategies is a major clinical 
challenge. Here, we identify sorafenib as an activator of AMP-activated protein 
kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We 
further show in a phase II clinical trial in KRAS mutant advanced non-small cell 
lung cancer (NSCLC) with single agent sorafenib an improved disease control rate 
in patients using the antidiabetic drug metformin. Consistent with this, 
sorafenib and metformin act synergistically in inhibiting cellular proliferation 
in NSCLC in vitro and in vivo. A synergistic effect of both drugs is also seen 
on phosphorylation of the AMPKα activation site. Our results provide a rationale 
for the synergistic antiproliferative effects, given that AMPK inhibits 
downstream mTOR signaling. These data suggest that the combination of sorafenib 
with AMPK activators could have beneficial effects on tumor regression by AMPK 
pathway activation. The combination of metformin or other AMPK activators and 
sorafenib could be tested in prospective clinical trials.