title: Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation.
abstract: 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.
authors: Division of Molecular Carcinogenesis, Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Floris H
authors: FH
authors: Groenendijk
authors: Wouter W
authors: WW
authors: Mellema
authors: Eline
authors: E
authors: van der Burg
authors: Eva
authors: E
authors: Schut
authors: Michael
authors: M
authors: Hauptmann
authors: Hugo M
authors: HM
authors: Horlings
authors: Stefan M
authors: SM
authors: Willems
authors: Michel M
authors: MM
authors: van den Heuvel
authors: Jos
authors: J
authors: Jonkers
authors: Egbert F
authors: EF
authors: Smit
authors: René
authors: R
authors: Bernards
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000151:congenital* / Q000188:drug therapy* / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D009536:Niacinamide; D008687:Metformin; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: AMP-activated protein kinase; metformin; non-small cell lung cancer; salicylate; sorafenib