title: Phenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma.
abstract: Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Preclinical studies suggest that extracellular signal-regulated kinase (ERK) inhibitors are likely to provide benefit, albeit with limited efficacy as a single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. A combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis. Treatment with both drugs was required to fully suppress mechanistic target of rapamycin signaling, a known effector of NF1 loss. Mechanistically, SCH772984 increased the oxygen consumption rate, indicating that these cells relied more on oxidative phosphorylation upon treatment. Consistently, SCH772984 increased expression of the mitochondrial transcriptional coactivator peroxisome proliferator-activated receptor gamma, coactivator 1-α. In contrast, cotreatment with phenformin, an inhibitor of complex I of the respiratory chain, decreased the oxygen consumption rate. SCH772984 also promoted the expansion of the H3K4 demethylase KDM5B (also known as JARID1B)-positive subpopulation of melanoma cells, which are slow-cycling and treatment-resistant. Importantly, phenformin suppressed this KDM5B-positive population, which reduced the emergence of SCH772984-resistant clones in long-term cultures. Our results warrant the clinical investigation of this combination therapy in patients with NF1 mutant melanoma.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Trousil
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA; Department of Dermatology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Chan
authors.initials: C
authors.lastname: Mu
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Shaw
authors.affiliation: Division of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Division of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Tiwari
authors.initials: T
authors.lastname: Shakuntala
authors.affiliation: Division of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Dieter
authors.initials: D
authors.lastname: Manstein
authors.affiliation: Division of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Zippin
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. Electronic address: bin.zheng@cbrc2.mgh.harvard.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics*; D010101:Oxygen Consumption / Q000187:drug effects; D010629:Phenformin / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D007191:Indazoles; D025542:Neurofibromin 1; D010879:Piperazines; C587178:SCH772984; D010629:Phenformin; D048049:Extracellular Signal-Regulated MAP Kinases