Sebastian Trousil, Shuang Chen, Chan Mu, Fiona M

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Phenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma Sebastian Trousil, Shuang Chen, Chan Mu, Fiona M. Shaw, Zhan Yao, Yuping Ran, Tiwari Shakuntala, Taha Merghoub, Dieter Manstein, Neal Rosen, Lewis C. Cantley, Jonathan H. Zippin, Bin Zheng Journal of Investigative Dermatology Volume 137, Issue 5, Pages 1135-1143 (May 2017) DOI: 10.1016/j.jid.2017.01.013 Copyright © 2017 The Authors Terms and Conditions

Figure 1 Phenformin and SCH772984 synergistically inhibit proliferation in NF1-mutant cancer cells. (a) Mewo, (b) M308, and (c) SK-Mel-113 cells were treated for 72 hours with ERKi SCH772984 in the absence or presence of 1 mM phenformin and cell viability measured by MTS assay. One representative experiment of three is shown with n = 3 ± SD for each data point. (d) Synergy studies of SCH772984 and phenformin were carried out in various NF1-deficient cell lines according to the Chou-Talalay method and combination index (CI) calculated by CompuSyn. CI < 1 demonstrates synergism, CI = 1 additive effect, and CI > 1 antagonism. Mean of n = 3 ± SD. ERKi, ERK inhibitor; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; NF1, neurofibromin 1; SD, standard deviation. Journal of Investigative Dermatology 2017 137, 1135-1143DOI: (10.1016/j.jid.2017.01.013) Copyright © 2017 The Authors Terms and Conditions

Figure 2 Effect of combined SCH772984 and phenformin treatment on apoptosis, cell cycle, and mitochondrial metabolism. (a) Annexin V staining and (b) cell cycle analysis after treatment with SCH772984 (0.3 μM for both cell lines) and phenformin (Mewo, 1 mM; M308, 0.3 mM) for 48 hours. Mean of n = 3 ± SD. (c) OCR and (d) ECAR in Mewo cells on pretreatment with 0.3 μM SCH772984 and 30 μM phenformin for 24 hours and exposure to mitochondrial stressors oligomycin, FCCP, and rotenone/antimycin A (Rot/AntA). Mean of n = 5 ± SD. (e) PGC1α expression after treatment with inhibitors in Mewo (0.1 μM SCH772984) and M308 (1 μM SCH772984) cells for 24 hours. *P ≤ 0.05; ***P ≤ 0.001; ****P ≤ 0.0001. ECAR, extracellular acidification rate; FCCP, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; OCR, oxygen consumption rate; PGC1α, peroxisome proliferator-activated receptor gamma, coactivator 1-α; SD, standard deviation. Journal of Investigative Dermatology 2017 137, 1135-1143DOI: (10.1016/j.jid.2017.01.013) Copyright © 2017 The Authors Terms and Conditions

Figure 3 mTOR signaling is cooperatively suppressed by SCH772984 and phenformin. (a) Mewo, (b) M308, and (c) SK-Mel-113 cells were treated with indicated doses of inhibitors (Mewo, 0.1 μM SCH772984; 0.3 mM phenformin; M308 and SK-Mel-113, 1 μM SCH772984; 1 mM phenformin) for 24 hours and subjected to western blotting with indicated antibodies. ACC, acetyl-CoA carboxylase; AMPK, AMP-activated kinase; ERK, extracellular signal-regulated kinase; mTOR, mechanistic target of rapamycin. Journal of Investigative Dermatology 2017 137, 1135-1143DOI: (10.1016/j.jid.2017.01.013) Copyright © 2017 The Authors Terms and Conditions

Figure 4 Phenformin inhibits expansion of KDM5B-positive cells on SCH772984 treatment. (a) Scheme of KDM5B-reporter construct. (b) Mewo and (c) M308 cells stably transduced with the KDM5B reporter were treated with 0.3 μM SCH772984 in the absence or presence of 1 mM (Mewo) or 0.3 mM (M308) phenformin for 72 hours and distribution of KDM5B-positive cells compared with vehicle-treated controls. Mean of n = 3 ± SD. Representative FACS plots are shown. *P ≤ 0.05; **P ≤ 0.01. FSC, forward scatter; GFP, green fluorescent protein; ns, nonsignificant; SD, standard deviation. Journal of Investigative Dermatology 2017 137, 1135-1143DOI: (10.1016/j.jid.2017.01.013) Copyright © 2017 The Authors Terms and Conditions

Figure 5 Phenformin and SCH772984 synergistically inhibit emergence of resistant clones in NF1-deficient cancer cells. Clonogenic growth assays were carried out in Mewo (0.3 μM SCH772984, 0.3 mM phenformin for 11 days), M308 (0.3 μM SCH772984, 30 μM phenformin for 14 days), SK-Mel-113 (1 μM SCH772984, 0.3 mM phenformin for 11 days), and WM88 (0.03 μM SCH772984, 0.5 mM phenformin for 11 days) cells. NF1, neurofibromin 1. Journal of Investigative Dermatology 2017 137, 1135-1143DOI: (10.1016/j.jid.2017.01.013) Copyright © 2017 The Authors Terms and Conditions